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Role of immunotherapy in the treatment of cancer: a systematic review.

Simple Summary

1. introduction, 2.1. search strategy, 2.2. eligibility criteria, 2.3. selection and data collection process, 2.4. risk of bias assessment, 2.5. data analysis, 3.1. study selection, 3.2. reporting biases, 4. discussion, 5. limitations, 6. conclusions, author contributions, conflicts of interest.

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Ling, S.P.; Ming, L.C.; Dhaliwal, J.S.; Gupta, M.; Ardianto, C.; Goh, K.W.; Hussain, Z.; Shafqat, N. Role of Immunotherapy in the Treatment of Cancer: A Systematic Review. Cancers 2022 , 14 , 5205. https://doi.org/10.3390/cancers14215205

Ling SP, Ming LC, Dhaliwal JS, Gupta M, Ardianto C, Goh KW, Hussain Z, Shafqat N. Role of Immunotherapy in the Treatment of Cancer: A Systematic Review. Cancers . 2022; 14(21):5205. https://doi.org/10.3390/cancers14215205

Ling, Sia Pei, Long Chiau Ming, Jagjit Singh Dhaliwal, Madhu Gupta, Chrismawan Ardianto, Khang Wen Goh, Zahid Hussain, and Naeem Shafqat. 2022. "Role of Immunotherapy in the Treatment of Cancer: A Systematic Review" Cancers 14, no. 21: 5205. https://doi.org/10.3390/cancers14215205

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IMMUNOSUPPRESSIVE MECHANISMS IN THE TUMOR MICROENVIRONMENT MEDIATING RESISTANCE TO IMMUNOTHERAPY

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• Affiliation: School of Medicine, Department of Microbiology and Immunology
• Breast cancer is the leading site of new cancer cases in women and the second leading cause of cancer related deaths. Improvements in detection and treatment in the past three decades has led to a significant decline in breast cancer deaths, yet just this year more than 42,000 people are expected to die from breast cancer. Immunotherapy, boosting the anti-tumor immune response, is a valuable advancement for the field of cancer therapy. Immune checkpoint therapy focuses on blocking inhibitory receptors expressed on activated immune cells. Two prominent checkpoint inhibitory receptors are cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Unfortunately, most triple negative breast cancer patients do not benefit from immune checkpoint inhibition despite immune infiltration into the tumors. In the work presented here, we aim to find ways to improve immunotherapy through projects studying the effectiveness of immune checkpoint blockade in cancer. First, we evaluated several models of breast cancer and found the heavily immune infiltrated claudin-low subtype was not able to respond to immunotherapy due to the suppressive tumor microenvironment. This subtype of breast cancer responded to checkpoint inhibition only in the context of specific and complete regulatory T cell (Treg) depletion. Second, we studied the role of PD-1 blockade on Tregs in a model of claudin-low breast cancer. We found that PD-1 blockade increased proliferation and survival of Tregs in the tumor microenvironment, leading to increased immunosuppression. Third, we observed the role of PD-1 expression on NK cells in cancer and chronic viral infection. We saw that NK cells may not be a beneficial target for immunotherapy due to the inconsistency of PD-1 expression. Together, this work provides insight into potential mechanisms involved in the poor response to immune checkpoint therapy in some cancers. Although tumors may be heavily immune infiltrated, this does not predict response to immunotherapy, and a more thorough analysis of the tumor microenvironment should be done such as determining which subsets of immune cells in the tumor expressing PD-1 can potentially be affected by checkpoint blockade.
• Cancer Immunology
• Immunotherapy
• https://doi.org/10.17615/kp4y-f910
• Dissertation
• Serody, Jonathan S
• Wan, Yisong
• Vilen, Barbara
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Home > Student Publications and Other Works > Theses and Dissertations > Master's Theses > 4339

Master's Theses

Tumor immunology: understanding the immune system and cancer to enhance the efficacy of cancer immunotherapies.

Natasha Malibu Lenart Follow

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Master of Science (MS)

Molecular Biology

Tumor cells are notorious for their ability to escape immune surveillance, but developments in the understanding of the tumor microenvironment and how the immune system can be re-activated in tumors have had significant clinical impact. Commercially available and experimental methods such as adoptive cellular therapy, cytokine stimulation, and immune checkpoint blockade are promising immunotherapies for a variety of cancers, including solid tumors and hematological malignancies. However, induction of persistent, long-term anti-tumor immunity after initial treatment is infamously difficult. as a result, scientists are searching for new approaches to improve established immunotherapies. by employing combination treatments or enhancing the functionality of cellular products prior to infusion, patients may experience better clinical outcomes through the development of more effective immunotherapies. This thesis reviews the function of the immune system in the tumor microenvironment and discusses how this knowledge is used within the field of tumor immunology to develop and enhance immunotherapy models.

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Lenart, Natasha Malibu, "Tumor Immunology: Understanding the Immune System and Cancer to Enhance the Efficacy of Cancer Immunotherapies" (2020). Master's Theses . 4339. https://ecommons.luc.edu/luc_theses/4339

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Best Survival Outcomes With Neoadjuvant Immunotherapy in Melanoma

Liam Davenport

September 20, 2024

BARCELONA, SPAIN — Patients with high-risk stage III resectable melanoma treated with neoadjuvant combination immunotherapy achieved higher event- and recurrence-free survival than patients who received monotherapy with immunotherapy or a targeted agent or targeted therapy plus immunotherapy, according to a large-scale pooled analysis from the International Neoadjuvant Melanoma Consortium.

Importantly, the analysis — presented here at the European Society for Medical Oncology (ESMO) Annual Meeting 2024 — showed that achieving a major pathological response to neoadjuvant therapy is a key indicator of survival outcomes.

After 3 years of follow-up, the results showed that neoadjuvant therapy is not delaying melanoma recurrence, "it's actually preventing it," co-investigator Hussein A. Tawbi, MD, PhD, Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, told Medscape Medical News . That's "a big deal."

Since 2010, the introduction of novel adjuvant and neoadjuvant therapies for high-risk stage III resectable melanoma has led to incremental gains for patients, said Georgina V. Long, MD, PhD, BSc, chair of Melanoma Medical Oncology and Translational Research, The University of Sydney, Sydney, Australia, who presented the results.

The first pooled analysis of neoadjuvant therapy in 189 patients, published in 2021 , indicated that those who achieved a major pathological response — defined as either a pathological complete response (with no remaining vital tumor) or a near-complete pathological response (with vital tumor ≤ 10%) — had the best recurrence-free survival rates.

In the current study, the researchers expanded their cohort to include 818 patients from 18 centers. Patients received at least one dose of neoadjuvant therapy — either combination immunotherapy, combination of targeted and immunotherapy agents, or monotherapy with either an immune checkpoint inhibitor or a targeted agent.

The median age was 59 years, and 38% of patients were women. The median follow-up so far is 38.8 months.

Overall, the 3-year event-free survival was 74% in patients who received any immunotherapy, 72% in those who received immunotherapy plus a targeted BRAF/MEK therapy, and just 37% in those who received targeted therapy alone. Similarly, 3-year recurrence-free survival rates were highest in patients who received immunotherapy at 77% vs 73% in those who received immunotherapy plus a targeted BRAF/MEK therapy and just 37% in those who received targeted therapy alone.

Looking specifically at PD-1–based immunotherapy regimens, combination therapy led to a 3-year event-free survival rate between 77% and 95%, depending on the specific combinations, vs 64% with PD-1 monotherapy and 37% with combination targeted therapy.

Overall, patients who had a major pathological response were more likely to be recurrence free at 3 years. The 3-year recurrence-free survival was 88% in patients with a complete response, 68% in those with a partial pathological response, and 40% in those without a response.

Patients who received immunotherapy were more likely to have major pathological response. The 3-year recurrence-free survival was about 94% in patients who received combination or monotherapy with immune checkpoint inhibition, and about 87% in those who received immunotherapy plus targeted therapy. The recurrence-free survival rate was much lower in patients given only BRAF/MEK inhibitors.

The current overall survival data, which are still immature, suggested a few differences when stratifying the patients by treatment. Almost all patients with a major pathological response were alive at 3 years compared with 86% of those with a partial pathological response and 70% of those without a pathological response.

Overall, the results showed that immunotherapy — as either combination or monotherapy — is "quite a bit" better than targeted therapy with BRAF/MEK agents, which offers no substantial benefit, said Twabi.

"When you see the same pattern happening in study after study, in a very clear, robust way, it actually becomes very powerful," Twabi explained.

Rebecca A. Dent, MD, MSc, chair of the ESMO Scientific Committee who was not involved, told a press conference that the introduction of immunotherapy and combination immunotherapy has dramatically changed outcomes in melanoma.

Commenting on the current study results, Dent said that "combination immunotherapy is clearly showing exceptional stability in terms of long-term benefits."

The question now is what are the toxicities and costs that come with combination immunotherapy, said Dent, from National Cancer Centre Singapore and Duke-NUS Medical School, Singapore.

No funding declared. Long declared relationships with a variety of companies, including AstraZeneca UK Limited, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis Pharma AG, and Regeneron Pharmaceuticals Inc. Twabi declared relationships with Bristol Myers Squibb, Novartis, Merck, Genentech, GlaxoSmithKline, Eisai, and others. Dent declared relationships with AstraZeneca, Roche, Eisai, Gilead Sciences, Eli Lilly and Company, Merck, and Pfizer.

Send comments and news tips to [email protected] .

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Lowering cancer drug dose could open tumors to immunotherapy

by Harry Perkins Institute of Medical Research

Research undertaken at the Harry Perkins Institute of Medical Research in Perth has shown that administering anti-cancer drugs at a hundred-fold lower dose than standard protocols could improve the tumor's response to immunotherapy.

Perkins Head of Cancer Microenvironment, Professor Ruth Ganss from the University of Western Australia (UWA), said the new research had shown an alternative path to high doses of anti-cancer drugs to fight tough cancers like melanoma, brain cancer or pancreatic cancer.

Prof. Ganss has dedicated her life to studying the microenvironment around solid tumors. This microenvironment consists of "sticky" support tissue and blood vessels that feed the cancer and make the tumor impenetrable to cancer-fighting drugs and immunotherapy.

Prof. Ganss's latest research, published this week in the Journal of Clinical Investigation , showed that when the dose of anti-cancer drugs was considerably reduced, the tumor initially grew, but then the blood vessels surrounding the tumor normalized, allowing immunotherapy to penetrate the tumor and be more effective.

"The anti-cancer drugs we are interested in are already clinically approved, this opens the way for us to propose new dosing and timing protocols for patients," said Prof. Ganss.

"Our clinical collaborators have been excited by the results that show an alternative method of administering drugs and immunotherapy together.

"The next stage in our research is a clinical trial where we will analyze tissue samples in patients with these hard-to-treat cancers.

"My team and I are excited to have found new ways of modulating cancer blood vessels with already clinically approved drugs, and now we can hopefully produce an outcome which lends itself to better, more effective treatments for the very sick and prolonging their lives."

Two other researchers from the Perkins, Professor Jonas Nilsson, Head of Melanoma Discovery, and Professor Alistair Forrest, Head of Systems Biology and Genomics were among the research team, as well as scientists from the U.S. and Germany.

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Harnessing the immune system against cancer: current immunotherapy approaches and therapeutic targets

Affiliations.

• 1 Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India.
• 2 Department of Biochemistry, Sree Narayana College, Kollam, Kerala, 691001, India. [email protected].
• 3 Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala, 682041, India. [email protected].
• PMID: 34671902
• PMCID: PMC8605995
• DOI: 10.1007/s11033-021-06752-9

Cancer immunotherapy is a rapidly evolving concept that has been given the tag "fifth pillar" of cancer therapy while radiation therapy, chemotherapy, surgery and targeted therapy remain the other four pillars. This involves the stimulation of the immune system to control tumor growth and it specifically targets the neoplastic cells rather than the normal cells. Conventional chemotherapy has many limitations which include drug resistance, recurrence of cancer and severe adverse effects. Immunology has made major treatment breakthroughs for several cancers such as colorectal cancer, prostate cancer, breast cancer, lung cancer, liver cancer, kidney cancer, stomach cancer, acute lymphoblastic leukaemia etc. Currently, therapeutic strategies harnessing the immune system involve Checkpoint inhibitors, Chimeric antigen receptor T cells (CAR T cells), Monoclonal antibodies, Cancer vaccines, Cytokines, Radio-immunotherapy and Oncolytic virus therapy. The molecular characterization of several tumor antigens (TA) indicates that these TA can be utilized as promising candidates in cancer immunotherapy strategies. Here in this review, we highlight and summarize the different categories of emerging cancer immunotherapies along with the immunologically recognized tumor antigens involved in the tumor microenvironment.

Keywords: CAR T cells; CTLA-4; Cancer immunotherapy; Cancer vaccines; Checkpoint inhibitor; Cytokines; Monoclonal antibodies; Oncolytic viruses; PD-1; PD-L1.

© 2021. The Author(s), under exclusive licence to Springer Nature B.V.

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Conflict of interest statement

Conflict of interest The authors declare that they have no competing interests.

Working mechanism of CTLA-4 and…

Working mechanism of CTLA-4 and PD-1 on cancer cells. The activation of T…

Generation of CAR-T Cells for…

Generation of CAR-T Cells for immunotherapy. One form of adoptive cell therapy is…

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Immunotherapy after surgery helps people with high-risk bladder cancer live cancer-free longer

• Posted: September 16, 2024

240-760-6600

Adjuvant pembrolizumab helps people with muscle-invasive bladder cancer remain cancer-free longer than observation alone.

Results from a large clinical trial show that treatment with an immunotherapy drug may nearly double the length of time people with high-risk muscle-invasive bladder cancer are cancer-free following surgical removal of the bladder. Researchers found that postsurgical treatment with pembrolizumab (Keytruda), which is approved by the Food and Drug Administration (FDA) for treating at least 18 different cancers, was superior compared with observation. The study, led by researchers at the National Institutes of Health (NIH), was published Sept. 15, 2024, in the New England Journal of Medicine .

“This study shows that pembrolizumab can offer patients another treatment option to help keep their disease from coming back,” said lead investigator Andrea B. Apolo, M.D., of the Center for Cancer Research at NIH’s National Cancer Institute (NCI). “Extending the time that these patients are cancer-free makes a big difference in their quality of life.”

A diagnosis of muscle-invasive bladder cancer means the tumor in the bladder has invaded into and through the muscular layer of tissue that encases the bladder. The standard treatment for this form of bladder cancer is to surgically remove the entire bladder. To improve the chances of successful surgery and of eliminating any cancer cells that may have already escaped from the tumor, patients are given cisplatin-based chemotherapy for a period before surgery, known as neoadjuvant therapy, or after surgery, known as adjuvant therapy.

However, many people with muscle-invasive bladder cancer can’t take or refuse neoadjuvant chemotherapy with cisplatin. Others can’t tolerate adjuvant cisplatin-based chemotherapy. Still others, who despite having received neoadjuvant chemotherapy with cisplatin, have persistent muscle-invasive disease but can’t be treated again with adjuvant cisplatin-based chemotherapy. Historically, these groups of patients were instead carefully monitored to watch for signs of relapse.

As an alternative to observation, researchers have been investigating giving patients immunotherapy drugs after surgery to see if it can help them live longer without their cancer coming back.

In 2021, FDA approved nivolumab (Opdivo) as an adjuvant therapy for people with high-risk muscle-invasive bladder cancer after a clinical trial showed that this immune checkpoint inhibitor—a type of immunotherapy that releases the brakes of T cells so they can recognize and attack tumors—doubled the median length of time patients remained cancer-free compared with a placebo. Adjuvant nivolumab is now the standard of care in this setting.

In the current trial, researchers investigated whether the immune checkpoint inhibitor pembrolizumab would also be effective as an adjuvant treatment. They randomly assigned 702 patients with high-risk muscle-invasive bladder cancer who had undergone bladder-removal surgery to receive adjuvant therapy with pembrolizumab every three weeks for a year, or to observation for the same period of time. About two-thirds of the patients in the trial had completed neoadjuvant therapy with cisplatin.

After a median follow-up of almost four years, patients in the pembrolizumab group remained cancer-free for a median of 29.6 months, compared with 14.2 months for the observation group. Pembrolizumab was well tolerated, with the most common side effects being fatigue, itching, diarrhea, and an underactive thyroid.

In some cancer types, immune checkpoint inhibitors such as pembrolizumab are more effective against tumors that are PD-L1-positive—that is, the tumor cells produce a large amount of the PD-L1 protein on their surface, than those that don’t, or PD-L1-negative. So Dr. Apolo and her colleagues assessed whether the effect of pembrolizumab varied by PD-L1 status.

Among the 404 patients whose tumors were PD-L1-positive, those treated with pembrolizumab remained cancer-free for a median of 36.9 months, compared with 21 months for those in the observation group. Among the 298 patients whose tumors were PD-L1-negative, those treated with pembrolizumab remained cancer-free for a median of 17.3 months, compared with nine months for the observation group. The researchers concluded that PD-L1 status should not be used to select patients for treatment with pembrolizumab, as both groups benefited from adjuvant pembrolizumab.

In preliminary data on overall survival, at three years, about 61% of patients in the pembrolizumab group were still alive, compared with about 62% of patients in the observation group. The researchers pointed out that many patients in the observation group began taking nivolumab once it was approved or withdrew from the study, which may have skewed the results and made the overall survival data difficult to interpret.

Research teams are already building on the study’s findings by exploring adjuvant treatment using various combinations of drugs with immune checkpoint inhibitors. Researchers are also testing biomarkers to identify patients with high-risk muscle-invasive bladder cancer who could benefit most from adjuvant treatment of any kind and spare those who may not need it.

The study, known as AMBASSADOR, is sponsored by NCI. The study is being led and conducted by the NCI-funded Alliance for Clinical Trials in Oncology, and it includes participation by NCI’s National Clinical Trials Network as part of Merck’s collaboration with NCI through a Cooperative Research and Development Agreement.

About the National Cancer Institute (NCI): NCI leads the National Cancer Program and NIH’s efforts to dramatically reduce the prevalence of cancer and improve the lives of people with cancer. NCI supports a wide range of cancer research and training extramurally through grants and contracts. NCI’s intramural research program conducts innovative, transdisciplinary basic, translational, clinical, and epidemiological research on the causes of cancer, avenues for prevention, risk prediction, early detection, and treatment, including research at the NIH Clinical Center—the world’s largest research hospital. Learn more about the intramural research done in NCI’s Center for Cancer Research . For more information about cancer, please visit the NCI website at cancer.gov or call NCI’s contact center at 1-800-4-CANCER (1-800-422-6237).

About the National Institutes of Health (NIH):  NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit  nih.gov .

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Home > Cancer Research Catalyst > Finding Ways to Overcome Ovarian Cancer’s Resistance to Immunotherapy

Finding Ways to Overcome Ovarian Cancer’s Resistance to Immunotherapy

Nearly a half century ago, one of the founders of cancer immunology, Lloyd J. Old, MD, predicted that “there is something unique about a cancer cell that distinguishes it from normal cells, and that this difference can be recognized by the body’s immune system.” At the time, most of his colleagues disagreed. 

But Old was right. Harnessing the body’s natural ability to fight cancer cells turned out to be one of the greatest success stories in medical history. In the decade or so since they’ve become standard of care, cancer immunotherapies have revolutionized treatment. Patients with advanced forms of cancer such as melanoma and non-small cell lung cancer —disease states once associated with short-term survival—have achieved remarkable outcomes, some so long-lasting that patients have been considered cured.  

However, Old’s prediction arrived with a qualification. There’s no one single difference that distinguishes a cancer cell from a healthy cell; no centrally located “on-off” switch to activate everybody’s immune system. Instead, there’s a vast, complex, and far-flung network of immune triggers and processes , most of which we don’t fully understand. This could be why some cancers respond well to immunotherapy, while others strongly resist it.  

Ovarian cancer , a particularly lethal and difficult-to-treat disease, has thus far been highly resistant to immunotherapies. This is especially frustrating because certain ovarian tumor cells are bad at repairing their own DNA , a weakness known to make other cancers vulnerable to immunotherapeutic targeting.  

Fortunately, 2024 saw some new immunotherapy combinations make incremental yet important advances against this malignancy. Let’s take a look at a few.  

High Hopes, Low Response

Cancer of the ovaries, the deadliest form of gynecological cancer, has high survival rates if caught early . Unfortunately, it’s usually only diagnosed in its later stages because symptoms are often mild and vague and current screening methods are unreliable. Five-year survival rates of advanced ovarian cancer are below 30%. It is estimated that 19,680 women will be diagnosed with ovarian cancer in 2024 and 12,740 will die from it.  

Initial treatment usually involves removing the tumor via cytoreductive debulking surgery combined with platinum-based chemotherapy (such as cisplatin and carboplatin). Only a small percentage of patients with well-differentiated tumors confined to the ovaries will not need additional systemic treatment. This can take various forms.  

For example, an aggressive subtype of ovarian cancer called high-grade serous ovarian cancer (HGSOC), usually responds well to chemotherapy given after surgery. But about 20% of HGSOC cases are associated with mutations in the genes BRCA1 or BRCA2, which play a role in a DNA repair pathway called homologous recombination (HR), and ultimately promote cancer growth.  

A class of therapeutics called poly (ADP-ribose) polymerase (PARP) inhibitors disrupt the proteins that cancer cells use to fix their DNA. Multiple PARP inhibitors approved by the U.S. Food and Drug Administration (FDA) can treat BRCA-mutation positive and/or HR deficiency-positive ovarian cancers. While these drugs have led to improved outcomes, most patients with ovarian cancer eventually develop resistance and face disease progression.  

This is where researchers thought immunotherapy might step in and save the day. Cancers with DNA repair defects tend to be more responsive to therapies that target the immune system. It was hoped a class of drugs called immune checkpoint inhibitors (ICIs) would be effective. Unfortunately, ICIs have never achieved better than a 10% to 15% response rate in ovarian cancer, but researchers continue to develop strategies to overcome this resistance. It could be that we simply haven’t found the right combination therapy yet. After all, researchers point out , in even the most responsive tumor types, such as melanoma and lung cancer, only 20% to 40% of patients respond to single-agent ICIs.  

Another factor is probably the state of the tumor microenvironment (TME), which is the ecosystem of cells, molecules and blood vessels that surround and feed a tumor. For example, we know patients with an inflamed, immune-infiltrated TME—so called “hot” tumors—have a better prognosis than those with a TME that is less inflamed or “cold.”  

New Combination Therapy 

The protein p62 (SQSTM1) plays a role in selective autophagy , signal transduction , inflammatory response, and other processes that occur within a cell. Tumors require p62 to grow and spread, and almost all human tumors contain elevated levels of this protein. Heightened levels of p62 in ovarian cancer cells often indicate poor prognosis and resistance to platinum-based chemotherapies. Recent clinical trial data suggest that targeting p62 could be an effective therapeutic strategy for ovarian cancer. 

The trial evaluated Elenagen, an investigational treatment that uses an injectable, supercoiled circular DNA (or plasmid) to promote an immune response that would seek out and destroy cells expressing high levels of p62. The trial enrolled 40 patients with platinum-resistant ovarian cancer, with 20 patients receiving weekly injections of Elenagen plus the chemotherapy drug gemcitabine, and 20 patients receiving gemcitabine alone. 

According to results published in Frontiers in Oncology , gemcitabine alone produced an average progression-free survival (PFS) of 2.8 months. But when the chemotherapy was combined with Elenagen, the average PFS was 7.2 months, a statistically significant improvement. Additionally, nine patients in the Elenagen-gemcitabine combination group remained disease free for at least 30 months, the duration of the study. 

Finally, the study did not find increased toxicity when Elenagen was added to gemcitabine, an important finding since oncologists often discontinue immunotherapies due to toxicities.   

Starving ovarian Tumor Cells 

Malignant cancer cells can survive under harsh conditions. But that survival comes at a price. They need more energy and nutrients than healthy cells—and one mineral they need more of is iron. 

HGSOC is especially iron dependent, with HGSOC cells showing increased expression of the transferrin receptor, an iron importer, and decreased levels of the iron efflux pump ferroportin when compared to healthy ovarian tissue or even to low-grade serous ovarian cancer. 

A paper published in Cancer Discovery , a journal of the American Association for Cancer Research (AACR), in August found that malignant cells located in the ovarian tumor microenvironment overexpressed iron-related gene signatures. Further, the presence of gene signatures involved in transmembrane iron transport across the plasma membrane predicted reduced survival rates among HGSOC patients.  

This led the researchers to wonder if disrupting iron accumulation in the ovarian cancer TME might offer a new therapy approach. To test their hypothesis, they treated ovarian cancer mouse models with deferiprone (Ferriprox), an iron chelator (or reducer) approved by the FDA in 2011, both alone and in combination with the platinum-based chemotherapy agent, cisplatin.  

Deferiprone alone lowered the number of malignant cells in the peritoneal cavity and reduced the accumulation of ascites, an immunosuppressive peritoneal fluid associated with drug resistance and metastatic disease. The drug slowed the cancer’s spread and decreased tumor-induced enlargement of the spleen. Treated mice showed about 25% increase in median survival over untreated mice. When combined with cisplatin, deferiprone-treated mice experienced about 50% increase in median survival.  

The researchers believe deferiprone works by inducing mitochondrial stress that causes mitochondrial DNA to leak into the cytoplasm, ultimately activating an antitumor immune response that boosts the efficacy of first-line chemotherapy.  

FDA-approved, and widely prescribed to patients with transfusional iron overload, deferiprone “might be repurposed as a new immunotherapeutic agent to treat patients with metastatic ovarian cancer,” the paper concluded.  

Making Tumors ‘Hot’ 

A new experimental drug, TILT-123, a virus engineered to attack tumor cells, works by selectively replicating in cancer cells and producing the cytokines tumor necrosis factor alpha and interleukin-2. Viral replication leads to cell lysis, and when the cell ruptures, these cytokines spill out into the TME, causing it to become inflamed, or “hot.” Researchers hope such hot tumors will amplify the strength of ICIs and other immunotherapies in ovarian cancer.  

In a phase I clinical trial presented at the AACR Annual Meeting 2024 , held April 5-10, 15 patients with ovarian cancer received the new therapy along with pembrolizumab (Keytruda), an ICI. Eight of the 12 evaluable patients showed stable disease, and researchers encountered no dose-limiting side effects. Both injected and non-injected tumors displayed robust immunological activity, and researchers are investigating whether certain immune biomarkers can predict clinical response to the treatment.  

Another potential way to inflame tumors is by altering gene expression in the TME. An abstract presented at the same conference looked at tumor samples from 30 patients who participated in a phase II clinical trial evaluating ICI in combination with azacitidine, a chemotherapy drug that also functions as an epigenetic modulator. Researchers examined 72 serial tumor samples collected prior to treatment initiation and after six weeks of therapy found upregulation of inflammatory and cytolytic (or cell destroying) genes. They also found upregulation of the co-inhibitory molecule CTLA-4 , in addition to many other inflammatory biomarkers and greater density of tumor-infiltrating immune cells in samples collected during treatment. 

Combining an epigenetic modulator and ICI therapy “induces an inflammatory response and reshaping of the tumor microenvironment that may enhance their clinical efficacy,” the authors concluded, “highlighting the therapeutic potential of utilizing epigenetic modulators as a way to sensitize platinum-resistant ovarian cancer to immune checkpoint inhibition.”  

The AACR is collaborating with the Rivkin Center to host the  15th Biennial Ovarian Cancer Research Symposium , in Seattle, Washington on September 20-21, for researchers to learn about the latest advances related to ovarian cancer and network with others in the field. 

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• v.10(6); 2020

Cancer immunotherapy: a promising dawn in cancer research

Banashree bondhopadhyay.

1 Division of Molecular Oncology and Cellular & Molecular Diagnostics, National Institute of Cancer Prevention and Research (NICPR), Noida, India

Sandeep Sisodiya

Atul chikara.

2 All India Institute of Medical Science (AIIMS), New Delhi, India

Pranay Tanwar

3 Sher-i-Kashmir Institute of Medical Sciences Soura (SKIMS), Srinagar, Jammu and Kashmir, India

4 Department of Surgical and Perioperative Sciences, Umea University, Sweden

Usha Agrawal

5 National Institute of Pathology, New Delhi, India

Ravi Mehrotra

Showket hussain.

Cancer is a highly proliferative disease, which is caused due to the loss of regulation of cell cycle and apoptosis, DNA damage, faulty repair system etc. The cancer microenvironment plays a pivotal role in disease progression as they contain different types of innate and adaptive immune cells. The most important molecules that establish a correlation between inflammation, innate immunity, adaptive immunity, and cancer are the molecules released by inflammatory cells in cancer microenvironment. These molecules secreted by the immune cells, which might activate a pro-tumorigenic and anti-tumorigenic response in cancer. In inflammatory microenvironment, the equilibrium state of immunosuppressive and immunostimulatory signals are important in tumor suppression. The immunotherapeutic approaches could be more effective in cancer treatment. However, advancement in immunobiology and cancer are improving the prospects of immunotherapy alone and/or in combination with the conventional therapies. Thus, the review attempts to highlight a promising and futuristic immunotherapeutic approach in combination with conventional treatment modalities.

Introduction

The immune system plays a crucial role in infection. It acts in a cascade manner to counter the pathogenic response both by the innate and adaptive immune systems [ 1 ]. They work in tandem to protect the host by specialized immune cells acting in the tumor microenvironment [ 1 , 2 ]. Innate immunity is the forefront protector in our body that generally protects the host by combating harmful microbes and helps in tissue repairing. Adaptive immunity comes into play when innate immunity breaks down and not capable to protect the body, which is based on antigen-specific receptors expressed on clonally expanded B and T lymphocytes. When innate immunity recognizes an infection or tissue injury, it recruits cells like macrophages, fibroblast, mast cell, dendritic cells, and leukocytes (monocytes and neutrophils) [ 2 ], which recognizes pathogenic determinants by PAMPs present on microbial nucleic acids, lipoprotein and carbohydrates. It also recognizes intracellular damage by DAMPs, released from injured tissues, with the help of intracellular and surface-expressed PRRs present on these cells. Furthermore, the activated PRRs then activate downstream transcription factors like NF-ĸB, AP-1, CREB, IRF etc. which gets activated and recruit leukocytes at the site of injury to repair microenvironment around the damaged tissue [ 2 ]. Thus, the activated leukocytes secrete pro-inflammatory cytokines (TNFα and IL1) and various chemokine’s that initiate the downstream effector cells, which are required for acute or chronic inflammation. Normally, anti-inflammatory cytokines are released after pro-inflammatory cytokines, which combat the effect of pro-inflammatory cytokines. Inflammation has pro-tumorigenic effects as well as anti-tumorigenic effects which are used in cancer immunotherapy [ 3 ]. Host defense response normally shares the process of acute inflammation while chronic inflammation is a prolonged inflammation that can lead to cancer [ 4 ]. Nearly onethird of cancers are found to be linked with chronic inflammation [ 5 ]. A deregulated molecular pathways maintains the connection between the immune system and cancer in the tumor microenvironment; while considering the role of the immune system, inflammation and cancer are well documented [ 6 ]. This review provides holistic insights on the role of immune response in cancer and its futuristic manipulations highlighting the scope of immunotherapeutics in prevention and management of cancers.

Origin of immunotherapy and cancer

In 1909, Paul Ehrlich first suggested the idea of cancer immunotherapy and demonstrated that antibodies might have the ability to directly combat cancer cells [ 7 ]. Later, in 1950s, Burnet and Thomas hypothesized the concept of immune surveillance, according to which the immune system destroys malignant cells from primary cancer site before they become detectable tumors [ 8 ]. However, in 2001, Robert D Schreiber and his colleagues first used the term immunoediting in the light of cancer research to describe the phenomenon wherein tumors are characterized by the immune environment in which they form. In their study, they suggested that the immune response prohibited the development of carcinogen-induced sarcomas and spontaneous epithelial tumors. Besides, they also demonstrated that the tumor suppressor activity of the immune system is crucially reliant on IFN-γ, which partially helps in regulating the immunogenicity of tumor cells. Schreiber and his group provided in experimental evidence supporting the concept of immune surveillance for cancer. However, they had also suggested that tumors developed in the presence of healthy immune system are less immunogenic compared to those that are developed in an immunocompromised host makes the immune system paradoxical in favoring the eventual growth of tumors leading to the escape of the immune response that is better able to escape the immune response [ 9 ]. The immune system has four basic tumor eradication strategies: 1) The host is protected from virus-induced tumors by immune shedding of viral load. 2) In case of inflammation, the rapid clearance of pathogens and response of inflammation prevents the inflammatory microenvironment from advancing into the tumor. 3) The immune system identifies explicitly TAAs or molecules secreted by cells under stress to kill tumors. 4) The immune system identifies precancerous and cancerous cells and eradicates them before the damage occurs [ 10 ]. As we all know, nothing is perfect in this world likewise, our body’s defense mechanism is not as perfect as it should be able to eradicate the cancer cells. As a result, some tumor cells take advantage and escape the immune surveillance to promote proliferation of the cancer cells. In addition, these tumors are less immunogenic to evade the immune response [ 11 ].

The genetic and/or epigenetic alterations in a normal cell transform them into cancer cells. Whereas, it is important to understand the biology of cancer cells which has two standard characteristic features: an uncontrolled cell division and their invasive ability either locally or at distant sites. It is well established that if oncogenes regulate cancer initiation then their progression is further guided by tumor microenvironment. In addition, the inflammatory cells can also influence cancer progression in the tumor microenvironment by distorting the metastatic ability of tumor cells [ 8 ]. The six known characteristic features of cancer are: unrestricted replication, predetermined growth signals, insensitivity to growth inhibitors, circumvents programmed cell death, blood vessel development, tissue invasion, and metastasis [ 9 ]; where in addition to these, cancer-related inflammation is now becoming seventh [ 12 ].

Recently, immunotherapy has shown positive patient outcomes in various clinical trials [ 13 ] wherein various exogenously modified immune molecules (interferons, interleukins and monoclonal antibodies) are being manipulated to provide better immune response over conventional therapies, such as chemotherapy/radiotherapy or both along with surgery. Immunotherapies are also recently used with adjuvants, which are termed as neo-adjuvant therapies. These therapies either encourage the activities of specific cells of the immune system or deactivate the signals produced by the cancer cells that help in suppressing the immune response. Therapies, including the endogenous immune mechanisms against cancer will act as a potent determinant to recognize the malignant cells as foreign agents. However, in order to achieve this, multiple immune pathways should be targeted simultaneously, which may offer better clinical outcomes.

Role of immune cells in cancer

As described in the previous section, the immune cells play a crucial role in carcinogenesis. Both innate immune cells (myeloid progenitors) and adaptive immune cells (lymphoid progenitors) participate either in cancer progression or cancer suppression. The innate immune cells act as the first line of defense against any pathogen which includes dendritic cells, macrophages, neutrophils, mast cells and natural killer cells, whenever, microenvironment around the normal tissue gets disturbed these cells secrete various cytokines, chemokines, growth factors and proteases which hampers the cascade of events that leads to inflammation. Also, the adaptive immune cell-like T-cells and B-cells react to tumor microenvironment, thus making a favorable environment for inflammatory response. These innate and adaptive immune cells in the tumor microenvironment communicate with the cancer cells and the surrounding stromal cells (mesenchymal cells) by autocrine and/or paracrine mechanism(s). In an aggressive and established tumor, the immune response generates towards the pro-inflammatory signaling which results in regression of these tumors very rarely. Both pro-tumor and anti-tumor immune responses co-exist with each other but which way the tumor has to progress is dependent on the tumor microenvironment [ 14 ]. Most of the immune cells are involved in the tumor microenvironment, where tumor-associated macrophages (TAMs) and T cells are mainly present in the area where the tumor is present. TAMs mostly promote tumor growth, angiogenesis, invasion and migration and their increased infiltration leads to the poor prognosis of cancer [ 15 ]. Mature T-cells are broadly categorized into two major types based on the presence of T cell receptors (TCR): γδ and αβ. αβ-T cells can be further divided into various subgroups like CD8 + cytotoxic T cells (Tc) and CD4 + helper T cells (Th). These Th cells further include Th1, Th2, Th17 and Treg, as well as NK cells. T cells can utilize both pro-tumor and anti-tumor effects [ 16 ], where an increase in T cell numbers can activate an increased population of Tc and Th cells which sometimes help in better survival of patients suffering from various types of cancers, melanoma, invasive colon cancer, multiple myeloma, and pancreatic cancers [ 10 ]. Sometimes, the lower number of Tc cell involvement increases the susceptibility in experimental animal models towards spontaneous or chemical carcinogenesis [ 9 ]. It has also been observed that in case of solid tumors, various T cell types (including CD8 + , Th1, Th2, Th17 cells) cause tumor progression [ 17 ]. Till now it has been reported that NK cells lack pro-tumorigenic role. Similarly, TAMs and lymphocytes also play a major role in tumor progression including Treg cells which act in a pro-tumorigenic manner by suppressing the antitumor immune responses [ 18 ]. Leucocytes forming the major group of the immune cells due to which these can be one of the important determinants among hallmarks of cancer as cancer-related inflammation is also considered as the seventh hallmark of cancer [ 19 , 20 ]. Previously, it was believed that the leucocytes help in immune surveillance to eradicate the tumor, but their diverse role has changed the concept in carcinoma-induced sarcomas and spontaneous epithelial carcinomas where they have shown protection against lymphocytes and IFN-γ [ 9 ]. In breast cancer, the occurrence of TILs with a high number of CD4 + /CD8 + and the Th2/Th1 ratio is one of the indicators of poor cancer prognosis [ 21 ]. Progression and metastasis of mammary cancer is stimulated by Th2 CD4 + T cells by targeting TAMs, giving rise to pro-angiogenic and pro-metastatic factors [ 22 ]. Similarly like these immune cells, breast cancer cells also produce several pro-tumorigenic cytokines and chemokines like IL-4, IL-6, IL-8 and CXCR-4, CCL-2, CCL-5 respectively; which cause tumor progression [ 23 ]. Till now, the degeneracy of T cell is not clear which arises various queries regarding the factors that determine the fate of T cell whether it will act as anti- or pro-tumorigenic in different types of cancers. As a consequence, these factors are one of the significant factors in immunotherapeutics. The above-mentioned phenomena may be collectively called as “tumorimmuno printing strategy” (TIPS); where both the innate and adaptive immune cells (dendritic cells, macrophages, neutrophils, mast cells, natural killer cells and lymphocytes) infiltrate the tumor stroma and making it more favorable for tumor progression and escape from a further immune response in the tumor microenvironment, and which may have a beneficial impact on both the diagnostic and prognostic approach for cancer management. TIPS may also be beneficial for clinicians and researchers to identify the purpose of various immune cells infiltrated in the tumor stoma, which may eventually dictate the tumor contents for advanced stages of carcinoma ( Figure 1 ).

The schematic representation demonstrates “tumor-immune printing strategy” (TIPS) the tumor microenvironment developing inside a human body and also representing the implication of immunotherapeutics to combat cancer. In the figure, the hexagonal boxes were used to express the various immunotherapies applied against various target molecules in the tumor microenvironment.

Immune cell infiltration and tumor microenvironment: from immune surveillance to immune editing

Recent studies have highlighted that the immune system may promote the emergence of primary tumor tissues and evade the immune selection process, rather than acting as a suppressor of the disease that might lead to the progression of cancer. Immune surveillance is known to regulate not only in host protection but also the advancement of the tumor in three major steps including elimination, equilibrium, and escape [ 24 ]. The process starts when the normal cells are induced to change into transformed cells. The first phase-elimination helps the cancer immune surveillance using extrinsic tumor suppressor response to clear out those transformed cells, thus, giving protection against cancer which is mostly T-cell dependent [ 10 ]. If the elimination process fails to clear the transformed cells, then the second phase, i.e., equilibrium comes in action, where cancer persistence occurs due to the genetic instability and immune response [ 25 ]. In which the transformed cells maintain their favorable microenvironment to expand their number for the maintenance of cancerous condition [ 24 ]. Tumor cells having reduced immunogenicity can survive better in an immunocompetent host however maintenance leads to the escape from immunological surveillance which allows third phase to act resulting in growth of the cancer [ 22 ]. During this phase, immune-edited cells grow uncontrollably through immune pressure determining as invasive tumors whereas in other models, a tumor-mediated active immunosuppression is found to enhance the tolerance level of tumor-specific T cell as a dominant immune escape mechanism [ 23 ]. In cancer patients, immunoediting shows the main effect of the “triple E” theory (elimination, equilibrium and escape) where clinically seeming tumors inherit the immune response resistance by escaping the adaptive immunity [ 24 ]. It can help the process of complete inalterability of most immunotherapies and vaccines for cancer therapy, in a small population of patients with even immunogenic diseases such as melanoma [ 25 ]. Neoplastic cells also have capability to enter the inflammatory pathways leading to tumor development by recruiting leukocytes, however, the underlying mechanisms in tumor-mediated inflammatory responses is still unclear. The innate immune cells belonging to myeloid lineage composed of TAMs and immature myeloid cells are found to be involved intrinsically [ 26 ]. These cells produce various chemokines, cytokines, proteases and several growth factors, which may promote tumor growth; and mediate local or systemic immunosuppression by inducing angiogenesis and tissue remodeling.

Advancement in cancer therapies

The most conveniently used therapies in cancer are chemotherapy/radiotherapy or both and surgery, that have shown moderate success in the treatment of advanced carcinomas. Despite the use of these conventional therapies as bridges, there is a gap in cancer therapeutic strategies for relapse-free survival of patients [ 26 ]. So to combat these drawbacks in the therapeutic strategies there is a need in the advancement of cancer therapy. In the current scenario, immunotherapy is emerging as a new strategy and various other types of immunotherapies are underway for treatment ( Table 1 ). Immunotherapy is combined with conventional therapies or used with adjuvants called neoadjuvant therapies. Therefore, cancer research is leading towards a better advancement in developing contemporary immunotherapies along with modified adjuvants. Adjuvant therapy is a process that includes improvement in a patient’s relapse free long-term survival chances after the patient undergoes primary therapy. Majorly, adjuvant therapies are considered to be systemic, where a substance travels through bloodstream targeting cancer cells in different parts of the body. The process involves chemotherapy, hormone therapy, radiation therapy, and a combination of various other therapies. Among several adjuvant therapies, such as adjuvant chemotherapy, in which drugs kills targeted cancer cells. Previous studies have shown that adjuvant chemotherapy may help in preventing cancer recurrence in early-stage breast cancer patients [ 27 ]. Generally, when more than one drug is given during adjuvant chemotherapy, it is known as combination chemotherapy [ 25 ] whereas, the hormonal therapy has been proven to be eminent in case of epithelial cancer like breast carcinoma. Tamoxifen has shown to reduce the level of estrogen, and it is already known that estrogen is suitable for the growth of the breast cancer cells. Previous studies have shown that tamoxifen helps in preventing the relapse of breast cancer [ 28 ]. Postmenopausal women are usually treated with aromatase inhibitors before or after tamoxifen treatment and instead of tamoxifen; some women are treated with trastuzumab, a monoclonal antibody that helps in reducing the level of Her2 [ 29 ]. Generally, radiation therapy is given after mastectomy or lumpectomy, but it is not given at the time of chemo or hormonal therapy. Neo-adjuvant chemotherapy refers to medicines given before surgery to treat breast cancer. Sometimes, it is used in women with large tumors who would have needed a mastectomy but may become a candidate for lumpectomy by reducing the size of invasive tumor before surgery. Both the adjuvant and neo-adjuvant therapies may have side effects depending on patient’s body physiology. Neo-adjuvant therapies are now being used more frequently than adjuvant therapies.

Different types of immunotherapy with their respective examples applied in various cancers

Immunotherapy

It is also known as biological therapy or biotherapy, which utilizes body’s own defense system to fight against diseases such as cancer. In immunotherapy, inhibitors of immune checkpoints are used to abolish the immune tolerance opted by some tumor cells [ 30 ]. Several types of immunotherapies have been routinely used such as monoclonal antibodies, cancer vaccines and non-specific immunotherapies. Various kinds of monoclonal antibodies are used in cancer treatment, like nude monoclonal antibodies, which work independently and no drug or radiolabeled substances are attached to it. For example, alemtuzumab is used to treat some patients suffering from Chronic Lymphocytic leukemia. It binds to CD25 antigen. Conjugated antibodies are targeted with chemotherapeutic drugs, radiolabeled toxic substances or any drug capable of killing cancer cells. For example, Brentuximab vedotin binds to CD30 antigen, and used against Hodgkin’s lymphoma. Bispecific monoclonal antibodies are made up of two parts that allows it to bind with two different proteins simultaneously. For example, Blinatumomab, which has two parts; one half binds to CD19 and the other half binds to CD3, and used to treat acute lymphocytic leukemia. Presently, immune inhibitors including monoclonal antibody are in use; for example, CTLA-4 is blocked with ipilimumab; and blocking of PD-1 receptor and the PD-1 ligand by antibodies like Nivolumab (BMS-936558) and MK-3475 (Merck) [ 31 ].

The understanding between the immune system and tumor is gradually improving. To withstand self-tolerance and restoration of homeostasis, a family of T-cells assists T-cell activation [ 32 ]. DCs and T-cells are the essential immune cells; thus, the recent approaches utilizing TLR signaling via TLR ligands to enhance the anti-tumor immune response [ 33 ]. In tumor microenvironment, TLR agonists induce Th1 antibody response and tumor antigen-specific CD8 + T cells to reduce the effect of cancer cells but then also the survivability and clinical response in the cancer patients is very poor; like utilization of TLR agonist against melanoma [ 34 ]. Therefore, the utilization of TLR agonist to treat cancer still needs research efforts and improvement to enhance its efficiency.

Targeted vaccination therapy

Previous studies have demonstrated that the regulation of tumor development is well performed by the immune system. It is also reported that adaptive immunity acts as a facilitator of “spontaneous” worsening of tumor cells [ 35 ]. The immune system has the notable quality to identify variety of antigens located on tumor cell surfaces, like TAAs [ 36 ]. Many predictions have been done by researchers and scientists regarding the vaccination therapy which suggests that this more reliable than standard therapies. From handling the cancer patients to their relapse-free survival, the immune system is necessary to produce a long-term and effective immune response against cancer cells by administering a vaccine. The tumor vaccination may also prove to be a promising strategy. The ideal tumor vaccine should have the ability to induce strong and long-lasting immune response against a broad spectrum of tumor antigens [ 24 ]. Scientists are also trying to develop therapy-based vaccinations against cancer cells that might activate the immune system to check the cancer cells. In addition, vaccines are also improvised against cancer cells with peptide-based vaccines, DNA-based vaccines, whole cell-based vaccines, dendritic cells-based vaccines, Anti-HER-2 vaccines, Anti-MUC-1 and Anti-CEA vaccines, and Anti-hTERT vaccines [ 37 ]. Cancer can also be caused due to viral and bacterial infections. So, in some cases vaccination might prevent infections that are causing cancers [ 38 ]. There are some strains of High-Risk Human Papilloma Virus (HR-HPVs), which causes cervical and other cancers [ 39 , 40 ]. Also, chronic infection, in patients with HBV has a higher chances of developing liver cancer [ 41 , 42 ], and chronic carrier state of Salmonella typhi has also been reported to be associated with gallbladder cancer [ 43 ]. But most of the cancers like colorectal, prostate, lung, and breast cancers, are not supposed to be caused due to infections. Doctors are not certain yet regarding the preparation of the vaccine against such type of cancers. Despite of being very promising, the availability of such vaccine will take longer time. Combining with other substances mainly with adjuvants result in enhancing the immune responses up to greater extent. As the immune system has special cells for memory, so researchers are predicting that it might continue to work for long from the time it is given. For example, FDA officially accepted Sipuleucel-T (Provenge®) as the sole vaccine for cancer treatment, thereby abandoning use of Hormonal therapy for advanced prostate cancer [ 44 ].

Non-specific cancer immunotherapies and adjuvants

This type of immunotherapies are not specific in their action against cancer cells, but stimulates a general immune system to work against cancer cells. Some cytokines, interleukins and interferons are used in this type of immunotherapy. In melanoma and renal carcinoma, a synthetically made IL-2 is allowed to treat the disease. Thus, IL-2 can be used alone or in combination with chemotherapy or with other cytokines such as IFN-α. Similarly, IL-2 and IFN-α is also taken up for the treatment of cancer. It may facilitate immune cells to win the battle against cancerous cells by hampering the growth process of cancer cells or inhibiting the blood vessels to help in providing nutrition to the tumor cells. The FDA approved some molecules for use in various types of cancer; for example, IFN-α can be used for the treatment of chronic myeloid leukemia, non-Hodgkin’s follicular lymphoma, cutaneous T-cell lymphoma, hairy cell leukemia, kidney cancer, melanoma and Kaposi’s sarcoma. Despite of having advantages of the above-mentioned drugs, they have their own side effects, which can be fatal for the survival of the cancer patients [ 45 ].

Advancement in immunotherapy: variety of cancer treating vaccines and emergence of oncolytic viruses and bacteria as an immunotherapeutic tool

Researchers are constantly working in the field of vaccine preparation that are assumed to treat various types of cancers. Among various types of such vaccines; the tumor cell vaccine would be highly promising, as it is being formed of cancer cells from the cancer patients and modified to be attacked by the patient’s immunological system and then injected back into the patient. The immune system targets these or any similar type of cells if persisting in the body. Antigen based vaccines are another type of vaccines that provokes the immune system utilizing only one or few groups of antigens, rather than exploiting the whole tumor cells. As these vaccines are mainly composed of peptides, they are also known as peptide-based vaccines, which are known to activate the immune response (including antibodies, Tc-cells and Th-cells) using antigenic epitopes derived from TAAs. Vaccines wherein DNA encoding the TAAs is taken up by APCs, are termed as DNA-based vaccines [ 46 ]. These DNAs will be delivered alone or in combination with other molecules through vectors, nanoparticles or lipoproteins. But in this case, researchers are still figuring out the selection of right vector because of its cumbersome delivery [ 47 ]. Dendritic cell vaccines utilize the DCs to raise both class-I and class-II immune response, which further activates the co-stimulatory molecules. This type of immune response can fight against the multiple targets in cancer [ 48 ]. Currently in the field of Immunotherapeutics, dendritic cell vaccines are proven to be one of the most successful molecule in treating cancer. For example; Sipuleucel-T (Provenge) is a dendritic cell vaccine, used to treat advanced prostate cancer [ 49 ].

Therapies other than radiation, chemo, hormonal, anti-angiogenic and targeted therapies; virotherapy is emerging as one of the promising immunotherapeutic approach in cancer treatment. Those viruses are termed as “oncolytic viruses” which target cancerous cells by evading the normal cells [ 50 ]. Examples of such oncolytic viruses contain herpes, measles, adenovirus, coxsackie virus, reovirus, poliovirus, poxviruses, and Newcastle disease viruses, which are part of clinical and preclinical development for cancer therapy [ 51 ]. Till date, the Food and Drug Administration (FDA) has approved only one oncolytic virus, a genetically modified form of a herpesvirus, for the treatment of melanoma. However, several viruses are being evaluated as a potential cancer treatment in clinical trials [ 52 ]. After infecting tumor cell, the virus copies itself multiple times until the tumor cell burst out and releases substances, such as tumor antigens, that allow the immune system to identify cancer. Thus, certain researchers consider tumor viruses to be a form of immunotherapy. The first oncolytic virus to receive FDA approval was for a skin cancer treatment known as Talimogene Lairbarybvic (Emilic®) or T-VEC; when injected into tumors produces a protein that stimulates the production of immune cells in the body and reduces the risk of developing herpes [ 53 , 54 ]. When it comes to oncolytic bacteria, attenuated Salmonella typhimurium and Clostridium novyi are being used in clinical trials to attack various types of cancer [ 55 ].

Cost-effectiveness of immunotherapy

Immunotherapy has proved to help in cure and manage many cancers like melanoma, lymphoma, lung, kidney, and bladder cancers. Doctors have witnessed that with the help of these immunotherapeutic drugs; patients were sent under remission for years rather than dying in short notice of time. But the main drawback of immunotherapy is their high cost, approximately $100,000 per patients that is a major hindrance in the field of immunotherapy. The average cost of cancer immunotherapy drugs has increased from $50,000 per patient in mid1990 to $250,000 today [ 56 ]. But when the medical facilities were added up with immunotherapy the prices soared up around $850,000 per patient. Most of the drug companies agree that their investment is too high to prepare these drugs in their R&D laboratories. For example, the making of drug “Kymriah”, Novartis is around $1 billion, but according to researchers at University of Pennsylvania, the total cost for removing, reprogramming, and injecting into the cells in each patient is less than $60,000 which is way less than the so-called high price tags. “Kymriah™ (CT019)” is a first ever artificially prepared CAR T-cell (Chimeric Antigen Receptor (CAR) T-Cell) therapy drug approved by FDA, and produced by Novartis for treating patients up to the age of 25 years with B-cell precursor or acute lymphoblastic leukemia (B-ALL) [ 57 ].

Over the past two years, the FDA has approved eight new immunotherapy drugs (MABS and NIBS), but the cost is still so high that it’s not affordable for normal people (https://blog.onco.com/immunotherapy-in-india-cancer-patients). In India, oncologists also agree on the cost-effectiveness of immunotherapy, the first therapy which is between 1-1.3 lakh depending on the patient’s weight, complemented with another therapy usually required after 21 days and stretching for 3-6 months depending on the patient’s condition [ 58 ].

Conclusion and future prospects

With the intervention of cost-effective and potential therapeutics, new strategies can be developed to bridge the lacunae surrounding the grey areas in the field of Immunotherapy. Moreover, with the advancement in strategies and technologies, immune cells can lead to the development of cost-effective immunotherapeutic strategies, which can be further used to develop personalized medicine based on tumor immune profiles of patients. Although, adjuvant therapies and other vaccinations are proving to be effective for treating metastatic carcinomas, furthermore there is a huge scope of developing vaccines with very limited side effects. Apart from the conventional methods of surgery, radiation and chemotherapy, cancer immunotherapies are highly expected to emerge as one of the efficient treatment options among all. This has also fueled conventional methods to increase long-term tumor reduction possibility among cancer patients, thereby creating an impactful treatment options.

Acknowledgements

Indian Council of Medical Research (ICMR), New Delhi, India.

Disclosure of conflict of interest

Abbreviations.

• News Releases

Immunotherapy after surgery helps people with high-risk bladder cancer live cancer-free longer

NIH clinical trial results expand treatment options for this disease

NIH/National Cancer Institute

Results from a large clinical trial show that treatment with an immunotherapy drug may nearly double the length of time people with high-risk, muscle-invasive bladder cancer are cancer-free following surgical removal of the bladder. Researchers found that postsurgical treatment with pembrolizumab (Keytruda), which is approved by the Food and Drug Administration (FDA) for treating at least 18 different cancers, was superior compared with observation. The study, led by researchers at the National Institutes of Health (NIH), was published Sept. 15, 2024, in the New England Journal of Medicine .

“This study shows that pembrolizumab can offer patients another treatment option to help keep their disease from coming back,” said lead investigator Andrea B. Apolo, M.D., of the Center for Cancer Research at NIH’s National Cancer Institute (NCI). “Extending the time that these patients are cancer-free makes a big difference in their quality of life.”

A diagnosis of muscle-invasive bladder cancer means the tumor in the bladder has invaded into and through the muscular layer of tissue that encases the bladder. The standard treatment for this form of bladder cancer is to surgically remove the entire bladder. To improve the chances of successful surgery and of eliminating any cancer cells that may have already escaped from the tumor, patients are given cisplatin-based chemotherapy for a period before surgery, known as neoadjuvant therapy, or after surgery, known as adjuvant therapy.

However, many people with muscle-invasive bladder cancer can’t take or refuse neoadjuvant chemotherapy with cisplatin. Others can’t tolerate adjuvant cisplatin-based chemotherapy. Still others, who despite having received neoadjuvant chemotherapy with cisplatin, have persistent muscle-invasive disease but can’t be treated again with adjuvant cisplatin-based chemotherapy. Historically, these groups of patients were instead carefully monitored to watch for signs of relapse.

As an alternative to observation, researchers have been investigating giving patients immunotherapy drugs after surgery to see if it can help them live longer without their cancer coming back.

In 2021, FDA approved nivolumab (Opdivo) as an adjuvant therapy for people with high-risk, muscle-invasive bladder cancer after a clinical trial showed that this immune checkpoint inhibitor—a type of immunotherapy that releases the brakes of T cells so they can recognize and attack tumors—doubled the median length of time patients remained cancer-free compared with a placebo. Adjuvant nivolumab is now the standard of care in this setting.

In the current trial, researchers investigated whether the immune checkpoint inhibitor pembrolizumab would also be effective as an adjuvant treatment. They randomly assigned 702 patients with high-risk, muscle-invasive bladder cancer who had undergone bladder-removal surgery to receive adjuvant therapy with pembrolizumab every three weeks for a year, or to observation for the same period of time. About two-thirds of the patients in the trial had completed neoadjuvant therapy with cisplatin.

After a median follow-up of almost four years, patients in the pembrolizumab group remained cancer-free for a median of 29.6 months, compared with 14.2 months for the observation group. Pembrolizumab was well tolerated, with the most common side effects being fatigue, itching, diarrhea, and an underactive thyroid.

In some cancer types, immune checkpoint inhibitors such as pembrolizumab are more effective against tumors that are PD-L1-positive—that is, the tumor cells produce a large amount of the PD-L1 protein on their surface, than those that don’t, or PD-L1-negative. So Dr. Apolo and her colleagues assessed whether the effect of pembrolizumab varied by PD-L1 status.

Among the 404 patients whose tumors were PD-L1-positive, those treated with pembrolizumab remained cancer-free for a median of 36.9 months, compared with 21 months for those in the observation group. Among the 298 patients whose tumors were PD-L1-negative, those treated with pembrolizumab remained cancer-free for a median of 17.3 months, compared with nine months for the observation group. The researchers concluded that PD-L1 status should not be used to select patients for treatment with pembrolizumab, as both groups benefited from adjuvant pembrolizumab.

In preliminary data on overall survival, at three years, about 61% of patients in the pembrolizumab group were still alive, compared with about 62% of patients in the observation group. The researchers pointed out that many patients in the observation group began taking nivolumab once it was approved or withdrew from the study, which may have skewed the results and made the overall survival data difficult to interpret.

Research teams are already building on the study’s findings by exploring adjuvant treatment using various combinations of drugs with immune checkpoint inhibitors. Researchers are also testing biomarkers to identify patients with high-risk, muscle-invasive bladder cancer who could benefit most from adjuvant treatment of any kind and spare those who may not need it.

The study, known as AMBASSADOR, is sponsored by NCI. The study is being led and conducted by the NCI-funded Alliance for Clinical Trials in Oncology, and it includes participation by NCI’s National Clinical Trials Network as part of Merck’s collaboration with NCI through a Cooperative Research and Development Agreement.

About the National Cancer Institute (NCI): NCI leads the National Cancer Program and NIH’s efforts to dramatically reduce the prevalence of cancer and improve the lives of people with cancer. NCI supports a wide range of cancer research and training extramurally through grants and contracts. NCI’s intramural research program conducts innovative, transdisciplinary basic, translational, clinical, and epidemiological research on the causes of cancer, avenues for prevention, risk prediction, early detection, and treatment, including research at the NIH Clinical Center—the world’s largest research hospital. Learn more about the intramural research done in NCI’s Center for Cancer Research . For more information about cancer, please visit the NCI website at cancer.gov or call NCI’s contact center at 1-800-4-CANCER (1-800-422-6237).

About the National Institutes of Health (NIH):  NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit  nih.gov .

New England Journal of Medicine

10.1056/NEJMoa2401726

Method of Research

Randomized controlled/clinical trial

Subject of Research

Article title.

Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma

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