Immunotherapy in Oral Cancer.

Immunotherapy is one of the newer entities which is promising, at least can be very much helpful as an adjuvant therapy. This newer modality of the treatment in the field of cancer treatment may be the fourth pillar supporting surgery, chemotherapy, and radiotherapy. Careful selection of patient is the key for success of immunotherapy, which is based on patient's immunological contexture. This review aimed to present the fundamental aspects of tumor immunity and immunotherapy, focused on oral squamous cell carcinoma.

INTRODUCTION

Immune system is the guardian of our body; it detects and destroys abnormal cells that are found in milieu. Abnormal cells may be foreign bodies, microorganisms, and even cancer cells. Ehrlich proposed that the immune system can search and attack transformed cells before any clinical presentation. Though cancer cells originate in the body, their genetic heterogeneity and components make them noticeable to the immune system. William Coley in 1891 found regression in cancer when he injected inactivated bacterial toxin (Coley’s toxin).[1] The immune system mainly comprises two arms, namely, innate and adaptive immunity.

The innate immunity encompasses macrophages, natural killer (NK) cells, dendritic cells, and eosinophils, and the adaptive immunity includes B and T lymphocytes, commonly known as B and T cells. B cells produce antibodies and T cells generate CD4+ and CD8+ cells. Cancer cells escape immune system by decreased expression of cell surface antigen, by secreting antigen that inactivates immune system, and by inducing microenvironment to secrete substances suppressing immune responses, thereby promoting tumor growth.[2]

Immunotherapy involves the stimulation of specific components of immune system, thereby strengthening it to counteract the signals that suppress the immune system.

IMMUNE SURVEILLANCE AND IMMUNE EDITING

The concept of immune surveillance was later discovered when the tumor-associated antigen was discovered in transplanted animal model.[3] The immune modulators such as levamisole were used for adjuvant therapy in colorectal cancers but had guarded results. Bacillus Calmette-Guérin (BCG), a well-known tuberculosis vaccine, has shown tumor regression in bladder cancer when injected intravesically.[4]

The immune surveillance has evolved into immune editing (a new concept put forward by Schreiber et al.[5]), which comprises three phases. The immunosurveillance or elimination phase is the first phase, in which the tumor growth is controlled by destruction of nascent cancer cells by T-cell activation via antigen presentation. Equilibrium phase is the second phase, which is characterized by tumor heterogeneity due to genetic instability of cells. In this phase, the tumor growth is in a steady state, either by growth enhancement or by inhibition. The escape phase is the final phase in which tumor cells escape or suppress immune system, thereby leading to tumor progression.[56]

TUMOR MICROENVIRONMENT

Recently, understanding of oncogenesis has changed its dimension, apart from tumor cells. Tumor microenvironment (TME) also plays a major role in tumor progression and its immunology. TME constitutes fibroblasts, stromal cells, immune cells, and endothelial cells, which actively take part in oncogenesis and immunology of tumor. The immune cells have promoting and inhibitory functions on tumor: M2 macrophages, myeloid-derived suppressor cells (MDSCs), regulatory T cells (Treg), and CD4 type 2 helper T cells(TH2) are promoter cells whereas NK cells, CD8+ T cells, M1 macrophages, CD4 type 1 helper T cells (TH1), and dendritic cells inhibit tumor. The tumor milieu is maintained by balance in protumor and antitumor immune cells, which in turn is governed by specific chemokines and adhesion molecules.[7] The immune cells can be found within tumor core, invasive front, or in tertiary lymphoid structures (TLS). The high endothelial venules are specialized vascular structures that surround the TLS and help in recruiting immune cells.[8] The understanding of “immune contexture” is essential in immunotherapy, the terminology that refers to the immune cells distribution in the core of the tumor and its microenvironment.[7]

IMMUNOTHERAPY

Immunotherapy can be broadly divided into active and passive.

Active immunotherapy involves attack of tumor cells by directing immune system (tumor as target). The immune cells were derived from blood or tumor of the patient, cultured in laboratory, and put back into the body, which in turn attack the tumor cells. In active immunotherapy, NK cells, dendritic cells, and cytotoxic T cells were commonly used.

Passive immunotherapy involves enhancement of immune system by targeting cell surface receptors, which in turn can form antibody-dependent cell-mediated (immunity) cytotoxicity (ADCC), for example, ipilimumab.

TYPES OF IMMUNOTHERAPY

Antibody-based therapies

Checkpoint inhibitors

Allison made a big breakthrough in the field of immune oncology by establishing a new concept that, apart from antigen presentation, activation of cytotoxic T cells needed a secondary costimulatory signal to achieve antitumor immunity.

The discovery of inhibitory pathways, which suppress T-cell activity leading to tumor growth, made a big revolution in the field of immunotherapy. Blocking these inhibitory pathways via monoclonal antibodies, which are otherwise called checkpoint inhibitors, has proved to be one of the best ways to regress tumor.[81011] Checkpoint inhibition has a variety of applications in immune oncology ranging from lung cancer to oral cancer.[12131415] Among checkpoint inhibitors, anti-CTLA-4 and anti-PD-1 antibodies are commonly used for therapeutic purposes. Anti-CTLA-4 antibodies have broader T cell function compared to anti-PD-1 antibodies, which reinstates that anti-CTLA-4 has more side effects than anti-PD-1. Recently, anti-PD-L1 ligand is in the late phase of commercial development for clinical practice with name durvalumab.

Ipilimumab was approved by the European Organisation for Research and Treatment of Cancer (EORTC) for the adjuvant therapy in patients with high-risk melanoma.[11] The combination of nivolumab and ipilimumab was approved in the United States for the treatment of BRAF-negative melanoma.[15] Apart from anti-PD-1 and anti-CTLA-4 antibodies, other checkpoint inhibitor receptors such as lymphocyte-activation gene 3 (LAG3), mucin domain 3 (TIM-3), and T-cell immunoglobulin have demonstrated therapeutic effects in clinical trials in combination with PD-1 agents.[161718] The combination of radiation and PD-1 blockade was proved to be synergistic in the treatment of cancer.[19]

Immune-related adverse reactions are common with checkpoint inhibitors, especially with anti-CTLA-4 antibodies, as these act in the priming phase. The autoimmune reactions manifested were hepatitis, rash, hypothyroidism, adrenal insufficiency, colitis, and so on.[20] Pembrolizumab was approved by the FDA for treating patients with recurrent head and neck squamous cell carcinoma (HNSCC).[21]

Targeted monoclonal antibodies

Monoclonal antibodies are made from either human or murine antibody components that bound to tumor-associated antigen leading to ADCC. The best example in this group which is used therapeutically is antibody against epidermal growth factor (EGFR). Deregulation of EGFR leads to the inhibition of apoptosis, invasion, metastasis, and angiogenic potential.[2223] Compared to normal mucosa, EGFR level is increased in 95% of HNSCC.[24] In HNSCC, the expression of EGFR is increased, which correlates with aggression of the cancer. EGFR is responsible for tumor progression in many solid tumors, especially in HNSCC.[25]

Monoclonal antibodies such as cetuximab and panitumumab are EGFR targeted therapies; they are proven to be effective against HNSCC either alone or in combination with radiotherapy.[26] Muc-1 levels are found to increase in HNSCC; antibodies against it have shown regression in the tumor in advanced cancer.[27] p53 is normally mutated in HNSCC; antibodies to mutated p53 proved to be useful in treating HNSCC with node involvement.[28]

Adoptive cell transfer

The importance of T cells in the elimination of cancer cells is a well-established phenomenon. T cells from tumor sample or blood of the patient are harvested, expanded, and reintroduced for antitumor immunity.[2930] The effectiveness of T cells can be accentuated by introducing specific antigen receptor into the cells by genetic engineering, thereby enhancing their ability to recognize tumor antigen.[31] Encouraging results were found in 93 patients treated for metastatic melanoma using adoptive cell transfer (ACT). This technique has proved excellent to treat metastatic solid tumors, which are otherwise difficult to treat with conventional techniques. ACT with human papillomavirus (HPV)–targeted tumor-infiltrating T cells has shown promising results in patients with cervical cancer.[32]

Improvements in ACT are gaining momentum because of its success rate; introduction of specific antigen receptor into T cells will help to kill cancer cells specifically.[31]

Large-scale production for clinical use of ACT is attempted by engineering antigen receptors: one technique is through accentuated presentation of major histocompatibility complex and the other is through chimeric antigen receptor (CAR). CAR T-cell immunotherapy is performed with help of viral vectors. The biggest advantage of this method is that it can be designed for specific tumor antigen.[333435]

Cancer vaccine

Cancer vaccines are made from patients’ tumor cells, which strengthen defense mechanism. These educate T cells to recognize and kill the cancer cells in the tumor.[36] Cancer vaccine is designed in such way that it contains a desired antigen, may be single antigen such as RNA, DNA, or peptides, or multiple antigens such as pulsed dendritic cells or whole cells.[3738] Vaccines can generate long-lived immunity with minimal toxicity and also can be combined with other immunotherapy techniques. However, these vaccines have some disadvantages such as they are expensive, cannot be used for fast-growing tumors, and take long time to get immune response.[3940]

Cancer vaccine types

Antigen vaccines: They are made up of specific antigens from patients’ tumor, which in turn can destroy cancer cells. With advancements in genetic engineering, large-scale production is feasible in future.

Dendritic cell vaccines: The role of dendritic cell to recognize and attack tumor cells is well understood. This vaccine, developed in laboratory, has a great potential in tumor regression.

DNA or RNA vaccines: These vaccines made of either DNA or RNA material proved to be excellent candidates for tumor regression.

Whole cell vaccines: Instead of specific antigens, DNA, or RNA, these vaccines are developed from entire cancer cells.

Cytokine immunotherapy

Cytokines are molecular messengers that allow the cells of our immune system to communicate with each other to generate a coordinated response to a target antigen (cancer cell). This immunotherapy stimulates immune cells through a complicated pathway, thereby increasing coordination between tumor cells and stromal cells. In recent years, a number of cytokines have been developed for the treatment of cancer. Two cytokines currently approved by the FDA for clinical purposes are interferon α (IFN α) and interleukin 2 (IL-2).

IFN α: These cytokines when injected subcutaneously in renal cell carcinoma have shown tumor regression. These have shown excellent results in stage 3 melanoma. The combination of IFN α and IL-2 showed partial response and higher toxicity.[41]

IL-2: It is an FDA-approved cytokine for metastatic melanoma. These cytokines increase level of NK cells and tumor-infiltrating lymphocytes (TILs) in the lesion.[4243] Perilymphatic IL-2 administration has increased the survival rate of patients with HNSCC;[44] increased tumor reactive T cells were found in patients who underwent monoclonal antibody therapy after surgery.[45]

The therapeutic application of cytokines is challenging because of their higher degree of pleiotropism. They act on many cell types in the body, which leads to many opposing effects such as diarrhea, fatigue, pancytopenia, and tiredness.

CONCLUSION

Cancer treatment is one of the challenging aspects in the medical field; the treatment modalities ranging from surgery to chemotherapy and radiation are yielding mixed results. To overcome this hurdle, newer innovative approaches are needed to reduce the morbidity and mortality of the patients. Immunotherapy is one of the newer entities that is promising, at least can be very much helpful as an adjuvant therapy.

The disadvantages of surgery such as recurrence of tumor or non-resectable lesion and toxicity of radiotherapy or chemotherapy can be substantially reduced by immunotherapy when used in combination with these treatment modalities. Scientists and clinicians are involved in more number of researches and preclinical and clinical trials in the field of immunotherapy. This newer modality of the treatment in the field of cancer treatment may become the fourth pillar supporting surgery, chemotherapy, and radiotherapy. Careful selection of patient is the key for success rate of immunotherapy, which is based on patient’s immunological contexture.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.