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REVIEW ARTICLE
Year : 2021  |  Volume : 17  |  Issue : 4  |  Page : 834-844

Cancer immunotherapy: Recent advances and challenges


1 Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
2 Department of Biochemistry, All India Institute of Medical Sciences, New Delhi; Department of Biochemistry, All India Institute of Medical Sciences, Guwahati, India
3 Department of Radiation Oncology, DRBRAIRCH, All India Institute of Medical Sciences, New Delhi; Department of Radiation Oncology, NCI, All India Institute of Medical Sciences, Jhajjar, Haryana, India

Date of Submission27-Aug-2020
Date of Decision05-Oct-2020
Date of Acceptance29-Dec-2020
Date of Web Publication12-Jul-2021

Correspondence Address:
Subhradip Karmakar
Department of Biochemistry, All India Institute of Medical Sciences, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1241_20

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 > Abstract 


Immunotherapy is a treatment that uses specific components of a person's immune system to fight diseases. This is usually done by stimulating or assisting one's immune system is attacking the offending agent – for instance, in the case of cancer – the target of immunotherapy will be cancer cells. Some types of immunotherapy are also called biologic therapy or biotherapy. One of the fundamental challenges that a living cell encounters are to accurately copy its genetic material to daughter cells during every single cell cycle. When this process goes haywire, genomic instability ensues, and genetic alterations ranging from nucleotide changes to chromosomal translocations and aneuploidy occur. Genomic instability arising out of DNA structural changes (indels, rearrangements, etc.,) can give rise to mutations predisposing to cancer. Cancer prevention refers to actions taken to mitigate the risk of getting cancer. The past decade has encountered an explosive rate of development of anticancer therapy ranging from standard chemotherapy to novel targeted small molecules that are nearly cancer specific, thereby reducing collateral damage. However, a new class of emerging therapy aims to train the body's defense system to fight against cancer. Termed as “cancer immunotherapy” is the new approach that has gained worldwide acceptance. It includes using antibodies that bind to and inhibit the function of proteins expressed by cancer cells or engineering and boosting the person's own T lymphocytes to target cancer. In this review, we summarized the recent advances and developments in cancer immunotherapy along with their shortcoming and challenges.

Keywords: Cancer vaccine, cancer, chimeric antigen receptor-T cells, immune check point, immunotherapy


How to cite this article:
Dhar R, Seethy A, Singh S, Pethusamy K, Srivastava T, Talukdar J, Rath GK, Karmakar S. Cancer immunotherapy: Recent advances and challenges. J Can Res Ther 2021;17:834-44

How to cite this URL:
Dhar R, Seethy A, Singh S, Pethusamy K, Srivastava T, Talukdar J, Rath GK, Karmakar S. Cancer immunotherapy: Recent advances and challenges. J Can Res Ther [serial online] 2021 [cited 2021 Nov 29];17:834-44. Available from: https://www.cancerjournal.net/text.asp?2021/17/4/834/321203




 > Introduction Top


Back in 2000, Hanahan and Weinberg proposed six hallmarks of cancer that constitute an organizing principle that provides a logical framework for understanding the remarkable diversity of neoplastic diseases.[1] Human tumor pathogenesis is a multistep process that the cancer cells acquired to become tumorigenic and ultimately malignant. These include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis [Figure 1]. Little did they realize then that this set of six rules was insufficient to explain the emerging ever-complex cancer pathogenesis world. This led to modifying their original hypothesis and incorporating additional attributes including two emerging hallmarks (deregulation of cellular energetics and avoidance of immune restriction), two enabling characteristics (genome instability and mutation and tumor-promoting inflammation). This understanding significantly added to the immune system's role in tumorigenesis and cancer treatment.[2]
Figure 1: The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors (modified from Hanahan and Weinberg, 2011)[2]

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Conventional cancer therapy using surgery, or chemotherapeutic agents, or radiation is primarily nonspecific and causes considerable side effects that often downgrade the quality of life (Agarwal 2016). While chemotherapy can kill cancer cells, it can affect cells with rapid turnovers such as the blood cells in the bone marrow and the cells in the gastrointestinal (GI) lining, skin, hair, and reproductive organs. When the healthy cells are damaged, this leads to side effects. Whether or not someone develops toxicity depends on the type and dose of drugs that are administered.


 > Cancer Surgery, Chemotherapy, Radiation, Refractory Cancer, and Measurable (or Minimal) Residual Disease Top


There are three primary modalities for cancer treatment – surgical management, chemotherapy, and radiation therapy. Which modality or combination of modality is employed in the treatment depends on several factors such as the site of the tumor, histopathological type, stage and grade, health status of the patient, etc. These primary modalities are not tumor specific and can affect the normal cells functioning in the vicinity of the tumor or elsewhere. Surgical management often requires a prolonged hospital stay and may lead to nonsalvage ability loss of typical structures, resulting in a reduction in life quality. Resistance to chemotherapy drugs is widespread. This often leaves a fraction of a tumor that either escapes the drug or is refractory/resistant to it due to various reasons.[3] It is this resistant population that is far more aggressive, which exhibits distant metastasis. Radiation therapy suffers from similar demerits. Radiation therapy damages cancer cells and can damage healthy cells in the treatment area.[4],[5] Side effects of radiation therapy depend on what part of the body receives radiation therapy. Different cells and tissues in the body cope differently with chemoradiation, with rapidly dividing cells like skin cells, cells lining the oral cavity and GI tract, and blood cells in the bone marrow been affected the most. Side effects usually happen during treatment and often get alleviated within a few weeks of treatment. Some side effects may persist even after the treatment is completed. If doses of radiation are high enough, some cells may not be able to repair themselves. As a result, the late effects of radiation effects may last for a long time or become permanent. In general, radiation therapy's side effects will depend on the type of radiation therapy. The part of the body is receiving the radiation, the amount (dose) of radiation and treatment schedule, and the patient's overall health status.

The term “refractory” usually applies to a disease that resists a specific treatment. For example, hormone-refractory prostate cancer refers to a disease that initially responds to drugs that block male hormones from fueling cancer. Still, eventually, the tumor becomes resistant to the treatment. When a patient's condition is or becomes refractory, what is usually followed in principle may be to try another form of approved treatment — called a second- or third-line therapy or enroll the patient in a clinical trial. For example, if a patient is diagnosed with refractory non-Hodgkin lymphoma (NHL), doctors may prescribe a second-line treatment with combinations of several chemotherapy agents; one such regimen is rituximab, ifosfamide, carboplatin, and etoposide. Sometimes, an intense second-line therapy for NHL is followed by a hematopoietic stem cell transplant for bone marrow rescue.

Minimal residual disease (MRD) refers to the persistence of a small number of cancer cells after the treatment.[6] Individual assays based on flow cytometry or polymerase chain reaction or deep sequencing are required to detect this condition, which is not infrequent in hematological malignancies such as leukemia,[7],[8] lymphomas,[8],[9] and myeloma. MRD possesses a risk for the relapse of the tumor and significant morbidity and mortality. Immunotherapy opens a paradigm in MRD cases, where targeting of residual cancer cells can be aimed at abrogating tumor relapses.


 > Changing Trend: Cancer Immunotherapy Top


Immunotherapy is now accepted as the fourth pillar of cancer therapy, with surgery, radiation, and traditional chemotherapy being the remaining pillars.[10],[11] The past decade has seen tremendous enthusiasm for immunotherapy in part due to observations that it consistently improves overall survival in select patients with historically refractory cancers that otherwise have an abysmal prognosis.[12] The immune system's concept can recognize and control tumor growth can be traced back to 1893 when William Coley used live bacteria as an immune stimulant to treat cancer. Still, the enthusiasm for cancer immunotherapy had been moderate due to its limited clinical efficacy.[13] This limited efficacy was due to tumor cells' ability to avoid recognition and elimination by the immune system, allowing them to become established in the host.[14],[15] However, tremendous progress has been made of late in understanding how cancer cells evade the immune system, the dynamics of T cell and target cell interactions, and regulatory T cells' role in modulating the immune system. Knowledge gained from these studies[16] offered new ways to stop immune evasion by cancer in favor of eliminating cancer cells[17] [Figure 2].
Figure 2: Timeline of CAR-T cell development (adapted from Hu et al., 2018)[17]

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There are several types of cancer immunotherapy. These include but are not limited to, monoclonal antibodies, checkpoint inhibitors, cytokines, vaccines, adoptive cell transfer, to name a few.


 > Basic Concepts Top


The immune system has two primary arms, innate (nonspecific/first to act) immunity and adaptive (specific/slow) immunity. Band T-cells are the foremost torchbearers for the adaptive immune response.[11],[14] The immune system plays three primary roles in the prevention of tumors. First, the immune system can protect the host from viral oncogenesis by eliminating or downsizing the viral infections. Second, through a timely elimination of pathogens and pathogen-induced inflammation, the immune system abrogates the inflammatory microenvironment conducive to tumorigenesis. Third, the immune system can accurately identify and eliminate tumor cells based on their expression of tumor-specific antigens – this essentially forms a part of cancer immune surveillance. In this process, the immune system identifies cancerous and precancerous lesions based on their expression of abnormal surface protein profiles. It eliminates them using various mechanisms that involve associated immune cells and the release of cytokines.[18] However, despite all these mechanisms in place, tumors do escape surveillance and develop, especially in the presence of a slightly compromised immune system.[19]


 > New Developments in Cancer Immunotherapy Top


Tumors use several mechanisms to evade the host immune response, including but not restricted to induction of anergy (unresponsiveness) in T cells, the release of immune-suppressive cytokines and local mediators to alter the tumor environment, etc. T-cells play a crucial role in cell-mediated immunity and recently, strategies to genetically modify T cells either through alteration of the specificity of the T-cell receptor (TCR) or through the introduction of antibody-like recognition domains in the form of chimeric antigen receptors (CARs) have made substantial advances.[20] These approaches are promising and have been demonstrated with success using engineered T-cells called CAR T-cells (CAR-T) to treat B-cell lymphomas. This clinical success is reflected in the growing number of users of this technology.

Tumor cells, over time, evolve ways to avoid immune surveillance, mostly from the T cells-mediated immune response.[19],[21],[22] This forms the central strategy in targeting immune checkpoint modulators in immunotherapy.[23] Antibodies that block these immune-modulatory proteins can either stimulate or inhibit the T-cell functions.


 > Tumor-Infiltrating Lymphocytes Top


Immunotherapy for cancer has generated a significant excitement owing to unprecedented responses in patients with chemotherapy-refractory acute leukemia and solid tumors.[24],[25] The mechanism of action for most immunotherapeutic techniques involves the activation of T-cell response against a malignancy. Cancer spread can be inhibited by blocking T-cell suppression signals (mediated mostly by T regulatory cells) or redirecting a T-cell to a tumor target with an antibody specific to T cells and tumors (such an antibody is known as a bi-specific antibody). In the case of adoptive T-cell therapies, a patient's T cells are isolated and manipulated in the laboratory and then reinfused back. The two main types of adoptive T-cell therapies employ either tumor-infiltrating lymphocytes (TILs) or CAR modified T-cells.

In TIL therapy,[26] TILs are isolated from solid tumors by surgery and expanded over several weeks ex vivo under sterile conditions using a cytokine cocktail to stimulate the T cells to generate a sufficient number of tumor-reactive T cells. Some patients with metastatic tumors experience durable complete remission, which is not possible with salvage chemotherapy (salvage therapy, also known as rescue therapy, is a form of treatment given after an ailment does not respond to standard treatment).

One of TIL therapy's significant disadvantages is the time required to generate a sufficient number of TILs to mediate treatment responses and GMP facility requirements. Even then, the expanded TIL seems to lose its killing capacity and seems to display a delayed reaction. This may explain why many patients have no antitumor effect from TIL therapy. Furthermore, requiring patients with the refractory disease to wait for TIL infusion is problematic for those who are very ill and when the requirement is more urgent.


 > Chimeric Antigen Receptor-T Cell Therapy Top


CART-cell therapy is a type of immunotherapy called “adoptive cell immunotherapy. “As ASCO President Bruce E. Johnson describes it, this technique “allows clinicians to genetically reprogram patients' immune cells to find and attack cancer cells throughout the body.” T cells engineered to express CARs induce high rates of clinical responses in patients with relapsed/refractory hematologic malignancies. They have demonstrated early indications of clinical activity in solid tumors.[27],[28],[29] The manufacture of CAR T-cell therapies presents significant and unique challenges. Although CAR-T cells are being used only recently in clinics, their concept is as old as the 1890s when scientists envisioned the body's own immune cells' enormous potential.

Depending on the nature of the CAR, CART therapy is classified into multiple generations.[30] In the first-generation CAR, the receptor consists of an scFv (single-chain variable fragment of the antibody) and the ITAM or immunoreceptor tyrosine-based activation motif of the TCR; the scFv is targeted against a tumor-specific antigen. In second- and third-generation CARs, one or two co-stimulatory molecules, respectively, are added. In the fourth and fifth generations, the single co-stimulatory molecule is supplemented with an interleukin (IL)-12 inducer or an IL-2 β-receptor motif, respectively.

The first two CAR-T therapies have recently been approved – the first from Novartis and the second from Gilead and Kite Pharma. The field is now booming, with over 240 CAR-T clinical trials running worldwide (https://labiotech.eu/car-t-therapy-cancer-review). In CAR, T-cell therapy persons' T-cells are removed by a leukapheresis process and taken to a laboratory.[31] The T cells are genetically altered so that they will attack cancer cells. These CAR T-cells are then expanded and are finally re-infused into the patient. One of this treatment regime's remarkable features is that it is often dubbed as a “living therapy.” CAR T cells typically have to be injected only once to get their full advantage. Essentially, this involves the following steps [Figure 3].
Figure 3: Workflow for chimeric antigen receptor-T cell therapy. It starts with isolating T cells from the blood withdrawn from a donor and engineering it in vitro to express chimeric antigen receptors on the surface of the cells. These clones are selected and re-infused back into the patients

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T cells collected from the patient

Through a process called apheresis, T cells are isolated from the blood drawn. The remaining blood is then returned to the body. All this process takes place in a sterile aseptic condition.

T cells are reengineered in a laboratory through recombinant DNA technology

Isolated T cells are then genetically engineered artificially in the laboratory by cloning to produce CARs on the cells' surface.

After this reengineering, the T cells are known as “chimeric antigen receptor T cells"

CARs are cell surface receptors that allow the T cells to recognize an antigen on the targeted tumor cells.

The reengineered chimeric antigen receptor T cells are then expanded

Patient-derived genetically modified T cells are later increased in the laboratory by the appropriate stimulation of these cells. Eventually, these CAR T cells are cryo frozen and sent to the clinic where they are being stored.

At the hospital or treatment center, the chimeric antigen receptor T cells are thawed and then infused into the patient

Many patients are given a brief course of one or more chemotherapy agents, called “lymphodepletion,” before receiving CAR T cells' infusion. CAR T cells that have been returned to the patient's bloodstream multiply in number. These are the “attacker” cells that will recognize and attack cells with the targeted antigen on their surface.

Immunotherapies based on checkpoint inhibitors have already been successful.[32],[33] They block a mechanism that tumor cells use to evade cell-mediated destruction (see next section). Immunotherapies based on CAR-T cells go one step further by engineering the T cells themselves to enhance the immune system's response against a specific tumor antigen. Although protocols and methodologies for manufacturing clinical-grade CAR T cells have now been established, CAR T cell therapies have been used to treat only a few hundred patients to date.[34] When expanding this state-of-the-art process to treat more patients in diverse types of cancers and at multiple centers, the process needs to be carefully evaluated to ensure production efficiency without compromising the final product's integrity and potency. Further considerations include generating a consistently high-quality vector for predictable genetic modification of cells and evaluating gene therapy safety and other regulations. So far, CARTs are only showing promise in blood-borne cancers such as lymphoma and acute lymphoblastic leukemia.


 > Immune Checkpoint Top


Immune checkpoints are negative regulators of the immune system, acting as self-protective defense buffers that play critical roles in maintaining self-tolerance, preventing autoimmunity, and protecting tissues from immune collateral damage.[35],[36] These immune checkpoints are often enhanced by cancers that allow them to avoid the antitumor immune system. Blocking immune checkpoints is thus a promising approach for activating antitumor immunity.[23]

To ensure that an immune-inflammatory response is not activated continuously once foreign or tumor antigens have stimulated an answer, multiple controls or “checkpoints” are in place or activated. These checkpoints are apart of the immunological synapses; the immunological synapses are formed by the interactions between (i) TCR and the peptide antigen on the target cell in the context of major histocompatibility complex (MHC), (ii) CD4 or CD8 on the T-cell with MHC, (iii) co-stimulatory signals mediated by molecules such as CD28 on T-cell and CD80/86 on the target cell, and (iv) various adhesion molecules. These synapses then regulate the T-cell functions that become specialized, or “polarized,” to perform different tasks.[37] As noted earlier, initial T-cell activation involves antigen presentation by the MHC molecules on the antigen-presenting cells to the corresponding TCR on naive T-cells. The interaction of the co-stimulatory TCR CD28 with the B7 ligand is required for full activation, which is tightly regulated or suppressed by inhibitory checkpoint receptor/ligand pairs to avoid collateral damage from autoimmunity.


 > Programmed Death Ligand 1/Cytotoxic T-Lymphocyte Antigen 4 Immune Checkpoint Inhibitors Top


Inhibitory receptors such as anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death1 (PD-1) expressed on tumor-specific T cells lead to compromised activation and suppressed effector functions such as proliferation, cytokine secretion, and tumor cell lysis.[38],[39] Modulating these receptors using monoclonal antibodies, an approach termed “immune checkpoint blockade,” has gained momentum as a new approach in cancer immunotherapy[40] [Figure 4]. This treatment concept was first introduced in patients with advanced melanoma: in this patient population, the anti-CTLA-4 antibody ipilimumab was the first drug ever to show improved overall survival in Phase III trials[41],[42] and was the first immune checkpoint inhibitor that was Food and Drug Administration (FDA) approved (in the year 2010). Antibodies directed against PD-1 and its ligand, programmed death ligand 1 (PD-L1), have shown much promise in treating melanoma,[42] renal cell cancer,[43],[44] nonsmall cell lung cancer (NSCLC),[45],[46] and other tumors, as evidenced by encouraging rates of the durability of tumor responses.[47] Because of the successes with immune checkpoint inhibitors in cancer immunotherapy, many new agents and strategies, including combination approaches, are being developed quickly. Cancer cells sometimes make a protein called PD-L1.[48] This protein can bind (attach) to a protein called PD-1 found on a normal immune cell.[49],[50] When these two proteins bind, it turns on a checkpoint. This slows the immune system and allows cancer to continue to grow. Some drugs target either the PD-1, while others act on PD-L1 protein. The drugs preclude the interactions between PD-1 and PD-L1.
Figure 4: Programmed death ligand 1 and cytotoxic T-lymphocyte antigen 4 interaction with T cells (adapted from: Oiseth et al., 2017)[40]

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While we often refer to anti-CTLA-4 and anti-PD-L1/PD-1 therapy interchangeably, fundamental differences do exist between these two treatments. While anti-CTL4Ab activates T cell-based immune response, the mechanism of anti-PDL1 Ab is different with different outcomes.[51] Distinctions in action, clinical efficacy, toxicity, and potential biomarkers for predicting response are crucial for future immunotherapy design. A priority is to expand the menu of checkpoint inhibitors, which currently includes Merck's Keytruda (pembrolizumab) and Bristol-Myers Squibb BMY - 0.07% Opdivo (nivolumab) – they work by inhibiting PD-1, an immune-suppressing protein, and are now used to treat several tumor types, including melanoma and lung cancer. Immuno-oncology researchers are searching for new checkpoints, in addition to testing various combinations of immune-boosting approaches in the hopes of making the therapies more effective.

Despite CTLA4 and PD-1 blockers' success, many patients do not respond to these treatments.[52] Furthermore, clinical benefit is still limited to a small subset of cancers, and only a minority achieves the promise of long-term survival.[53] It is, therefore, clear other immune checkpoint proteins mediate additional immune evasion mechanisms.


 > Additional Approaches Top


Researchers at the MD Anderson Cancer Center are studying the role of AM0010, an engineered form of IL-10, a protein that boosts the survival of cancer-killing CD8+ cytotoxic cells (https://www.mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail. ID2014-0495.html).[54],[55] They reported that, in 19 patients with advanced melanoma, renal cell carcinoma, or NSCLC, the agent alone or combination with chemotherapy produced a robust antitumor response without significantly magnifying side effects.

Treatment Regime: Pegilodecakin, Paclitaxel or Docetaxel and Carboplatin or Cisplatin, FOLFOX (Oxaliplatin/Leucovorin/5-Fluorouracil), gemcitabine/nab-paclitaxel, Capecitabine, Pazopanib, Pembrolizumab, Paclitaxel, nivolumab, Gemcitabine/carboplatin.


 > Cancer Vaccine Top


As mentioned previously, immunotherapy approaches rely on stimulating the body's immune system. Some immunotherapeutic agents target naturally occurring checkpoints that limit the anticancer activity of immune cells. Still, others, like the CAR-T-cell therapy recently approved to treat some types of leukemia and lymphomas, require a patient's immune cells to be removed from the body and genetically engineered to attack the tumor cells.[56],[57] Many of these approaches have been successful, but they each have downsides – from difficult-to-handle side effects to high-cost and lengthy preparation or treatment time. Prof Ronald Levy (Stanford University) proposed an innovative approach to reactivate the cancer-specific T cells-by injecting microgram amounts of two agents directly into the tumor site.[58] The first one, a short stretch of DNA called a CpG oligonucleotide, works with other nearby immune cells to amplify the expression of an activating receptor called OX40 on the surface of the T cells. The other component, an antibody that binds to OX40, activates the T cells to lead the charge against the cancer cells.[59],[60],[61] Because both the agents are injected directly into the tumor, only T cells that have infiltrated are activated. In effect, these T cells are “prescreened” by the body to recognize only cancer-specific proteins. The current clinical trial is expected to recruit about 15 patients with low-grade lymphoma. Prof. Levy proposes injecting these two agents into solid tumors in humans before surgical removal as a way to prevent recurrence due to unidentified metastases or lingering cancer cells or even to head off the development of future tumors that arise due to genetic mutations such as BRCA1 and BRCA2.


 > Oncolytic Viruses Top


These are an upcoming cancer therapy class that lies at the biologic and immunotherapy interface.[62],[63] In 2015, the US FDA approved the first oncolytic viral therapy in the United States, talimogene-laherparepvec (TVEC). In this process, viruses lacking virulence are genetically modified (to avoid killing normal cells) but can invade and destroy cancer cells.[64] Virus-mediated cell lysis is one of many mechanisms involved in the viral-induced killing of cancer cells. Oncolytic virus TVEC was recommended to treat advanced melanoma.[65],[66] These engineered herpes simplex-1 viruses are injected right into the melanoma site. These are programmed to express granulocyte-macrophage colony-stimulating factor (GM-CSF), which further activates the immune cells and stimulates them to proliferate. TVEC was approved based on data from OPTiM, a Phase 3 clinical trial that randomly assigned 436 patients 2:1 to receive TVAC plus GM-CSF or GM-CSF alone (Perez et al., 2018). Patients assigned to the experimental arm had a significantly higher durable response rate (16.3% vs. 2.1%; P < 0.001) and overall response rate (26.4% vs. 5.7%) compared with GM-CSF alone. Everyday adverse events with TVEC were fatigue, chills, and pyrexia. Clinical trials are underway with other oncolytic viruses to treat different types of cancer, with some of these protocols being combined with other types of cancer therapies.


 > Whole Tumor Cell Vaccines Top


Whole tumor cell vaccines are made from cancer cells collected during a biopsy or surgery.[67] Before they are injected back into the person, the cancer cells are irradiated to not form more tumors.[68],[69],[70] Antigens are still present on the surface of the cells and will stimulate an immune response. The immune system recognizes and attacks cancer cells containing these antigens. Whole tumor cell vaccines may be made from a person's tumor cells that were removed (autologous vaccine). Autologous vaccines are custom-made for each person. Since it is often difficult to get enough tumor cells from one person to make a vaccine, tumor cells taken from other people who have the same type of cancer are often used to make the vaccine (allogeneic vaccine).


 > Antigen Vaccines Top


Antigen vaccines use specific proteins or parts of proteins (antigens) from cancer cells' surface to stimulate the immune system to fight these cells.[71],[72],[73] Cancer cell antigens are sometimes mixed with substances to help the vaccine work better. These substances are called adjuvants, help the body to recognize the cells as foreign, so they boost the immune response—cytokines, such as IL-2, area type of adjuvant. The person with cancer is vaccinated with a mixture of cancer cell antigens and adjuvants. The immune system responds to both the adjuvant and the cancer cells that have the antigen. Some antigen vaccines cause an immune response to specific cancer. Others produce immune reactions to more than one kind of cancer.

Researchers are looking at ways of changing the antigens in cancer vaccines so that the immune system can recognize them more easily. They are also trying to incorporate combinations of several antigens in one vaccine to see if it will cause a response to an array of antigens that may be present on cancer cells.


 > Anti-Idiotype Vaccines Top


An idiotype is the part of an antibody determined by the complementarity determining region or CDR. Anti-idiotype vaccines indeed mimic the part of antigen to which the antibody specifically binds. Since they mimic antigens, an immune response is activated against these and against the antigen that is mimicked when these antibodies are administered. Anti-idiotype vaccines trigger an immune system response in almost the same way as antigen vaccines. When the vaccine is injected, it enables the immune system to recognize antigens on the cancer cells. B cells then produce antibodies against the cancer cell antigens.[74],[75],[76]


 > Dendritic Cell Vaccines Top


Dendritic cells (DCs) are a type of white blood cell that helps fight infection and tumors by boosting the immune response, particularly by forming a link between innate and adaptive immune systems. These cells are involved in antigen presentation to the T-cells and the activation of the latter. A dendritic vaccine uses cancer cells mixed with DCs to stimulate the immune system.

DC vaccines are custom-made for each person.[77],[78] Isolated DCs loaded with tumor antigen ex vivo and administered as a cellular vaccine have been found to induce protective and therapeutic antitumor immunity in experimental animals.[77] Some DCs are removed from a person's blood and are treated to make them multiply quickly. The cells are exposed to the cancer cell antigen, or their genetic makeup is changed so that they make the antigen. The DCs are then injected back into the person. They help the immune system recognize and destroy cancer cells that have the antigen. Sipuleucel-T (Provenge) is the first DC vaccine to be approved by the US-FDA. It is used in the treatment of advanced prostate cancer.[79]

DCs role in modulating the immune system and their role in improving cancer immunotherapy is a remarkable upcoming field.[80] Using different strategies involving the administration of antigens, along with immunomodulators, DC is activated. This concept is also used for the generation of DC-based vaccines. Our understanding and experience of different DC subsets and their dedicated function of cancer surveillance have aided in therapy development. However, the challenges for immunotherapy are enormous[81] and therefore need a considerable investment of time and expertise.


 > DNA Vaccine For Cancer Immunotherapy Top


A cancer vaccine's effect often becomes weaker as time goes by because the immune system eventually returns to its normal state of activity. Researchers are studying whether vaccines containing DNA can help the body maintain the immune response longer by providing it with a steady supply of antigens.[82],[83]

DNA vaccination in recent times has emerged as an attractive immunotherapeutic approach against cancer due to its simplicity, stability, and safety.[84],[85] Further, clinical trials have demonstrated that DNA vaccines have minimal adverse effects. DNA vaccines are also very cost-effective and can be administered repeatedly for long-term protection. Though it appears promising, DNA vaccines face challenges in inducing potent antigen-specific cellular immune responses due to immune tolerance against tumor-antigens. Several novel strategies to enhance the immunogenicity of DNA vaccines against tumors expressing self-antigens have been investigated. These include encoding of xenogeneic versions of antigens or fusing antigens with molecules that activate T cells (e.g., fusion proteins consisting of the ligand-binding domain of CTLA4 covalently attached to an antigen (Ag) are potent immunogens),[86],[87] or triggering associative recognition, or priming with DNA vectors followed by boosting with a viral vector, or utilization of immunomodulatory molecules.[88]

DNA inside cancer cells contains the genetic code for the proteins (antigens) that they make. Bits of DNA with the genetic instructions for one or more antigens may be used to make the vaccine.[85] The DNA for the vaccine is made in the laboratory. After a DNA vaccine is injected into a person, cells take up the DNA. These cells now have the instructions to complete the specific cancer antigen. This constant supply of antigens keeps the immune system actively fighting against the cancer cells.


 > Personalized Human Specific, Therapeutic Vaccine Top


Neoantigens have long been considered optimal targets for antitumor vaccines. Recent mutation coding and prediction techniques have aimed to streamline their identification and selection[69],[89],[90] reported the first-in-human application of a personalized neoantigen vaccine in patients with melanoma. Their vaccination strategy includes sequencing and computational identification of neoantigens from patients and designing and manufacturing a poly-antigen RNA vaccine for treatment.[91],[92]

Even though cancer therapy has made significant advances in the last decade, it still fails to achieve long-lasting responses in patients with metastatic disease in the majority of cases. One of the reasons for tumor relapse is intra-tumor heterogeneity, which is the basis for emerging tumor variants under targeted therapies and immunological pressures. Therefore, a personalized cancer vaccine promises to target multiple tumor-specific mutations, reducing side-effects by sparing normal tissue and keeping tumors under the control of immunological memory for as long as possible.


 > Challenges in Cancer Immunotherapy Top


Cancer immunotherapy has undoubtedly been one of the most promising and reliable treatment approaches.[93] It was even voted as a “breakthrough of the year” by Science in 2013[94] due to its innovative approach and enormous potential to cure cancer. This is further evident because the FDA currently approved several immunotherapeutic agents (including monoclonal Ab called checkpoint inhibitors). This involves agreeing to anti-CTLA4 Ab, Ipilimumab, anti PD1 receptor Ab, Nivolumab and Pembrolizumab, and anti-PD-L1 Ab, Atezolizumab, Avelumab, and Durvalumab as therapeutic options in several advanced cancers. These antibodies are proved to be beneficial against melanoma, head, and neck squamous cell cancer, NSCLC, urothelial cancer, Hodgkin lymphoma, and renal cell clear cell cancer.[95] Even with this progress, there are a lot of challenges and obstacles in immunotherapy. One of the critical metrics for a successful immune response against the tumor is the tumor mutational burden (TMB). Patients whose tumors present with significantly enhanced TMB and preexisting immune response signals can get real benefits from checkpoint inhibitors.[96],[97]

Further response to immunotherapy is subjected to individualistic variations. Hence, the outcome is often nonpredictable. Clinical benefits have been observed only in a minority of patients,[98] with not more than 15%–25% of subjects only responded to anti-CTLA-4 or PD-1/PDL1 therapy.

Even with all these variabilities, cancer per se is not inherently immunogenic. Even the cancer microenvironment can inhibit infiltrating T-lymphocytes, though a process called “immune evasion mechanisms” makes the antitumor responses dysfunctional.[99] Tumors, as we know, are highly heterogeneous. This, in turn, results in resistance to the treatment regime. Cancer signaling networks are remarkably flexible and adaptive in nature, so resistance is likely to develop to any single-targeted cancer treatment. We, therefore, can conclude that cancer immunotherapy comes with several challenges and obstacles, which makes its application quite limited. We hope that our more in-depth understanding of tumor, its microenvironment, and host immune surveillance can provide us with the necessary information to streamline the immunotherapy rationally and effectively.


 > Conclusion Top


Cancer immunotherapy is an upcoming new clinical approach that includes targeted antibodies, cancer vaccines, adoptive cell transfer, tumor-infecting viruses, checkpoint inhibitors, and cytokines to target and destroy cancer cells. Immunotherapies are classified as a type of biotherapy because these are derived from living organisms to fight cancer. Many immunotherapy treatments for preventing, managing, or treating different cancers can also be used in combination with surgery, chemotherapy, radiation, or targeted therapies to improve their effectiveness. Cancer immunotherapy may not cause the same side effects as chemotherapy and radiation, which may vary depending on the type of procedure performed.

Cancer immunotherapy is focused on the immune system and is often more targeted than chemotherapy or radiation.

  • Both chemotherapy and radiation damage healthy cells, commonly leading to hair loss and nausea/vomiting, side effects that may be less likely with immunotherapy
  • They are usually related to stimulation of the immune system, and side effects can range from minor inflammation symptoms to significant conditions similar to autoimmune disorders.


Given CAR T cells' success in treating patients worldwide with B-cell malignancies, scaling out CAR T-cell manufacturing capacity will allow examination of CAR T cell therapies' safety and efficacy in larger cohorts of patients worldwide. However, several manufacturing and regulatory challenges need to be considered when attempting to bring cellular treatment with a complex manufacturing process to a larger, international patient population.

Cancer immunotherapy was successfully used in hematological malignancies and some solid tumors[100],[101],[102] [Figure 5]. There have been several new monoclonal antibodies against cell cycle checkpoint targets, notably CTLA4 and PD1-PD-L1. This has resulted in FDA granting approvals for Ipilimumab (against CTLA4), Nivolumab, and Pembrolizumab (against PD1) and Atezolizumab, Avelumab, and Durvalumab (against PD-L1), as therapeutic options in several advanced cancers. These and other ongoing checkpoint inhibitors, for example, novel CTLA-4, PD-1, and PD-L1 inhibitors, are under development to treat patients with different types of cancer. More research is needed to identify novel targets and develop state or art technology to rapidly screen and validate these targets.
Figure 5: Chimeric antigen receptor-T cell therapy involves genetically engineering immune T cells to recognize specific proteins, or antigens, on tumor cells and attack them (inspired from: June et al. research publications)[100],[101],[102]

Click here to view


Acknowledgments

The authors would like to thank Dr Abhishek Shankar, MD(Preventive Oncology), LHMC, for critical discussion. We thank the Department of Biochemistry, All India Institute of Medical Sciences for providing infrastructure and facility.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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