Immunotherapy, the Next Generation of Cancer Treatment

Traditionally the basis of cancer treatment has consisted of surgery, radiation therapy, and chemotherapy. More recently, several promising treatment options have emerged in the field of immuno-oncology that point to the possibility of developing new methods of anticancer therapy. High-throughput, next-generation sequencing (NGS) has shown remarkable utility in cancer and immunology research, and contributed to the development of individualized immunotherapy. For example, NGS has dramatically improved our knowledge of the cancer genome and the intracellular mechanisms involved in tumor progression. Current methods of tumor analysis can effectively reveal new epitopes (neoantigens) that are possible targets for the immune system. Sequencing can also be used to determine the immune repertoire as a real-time, highly sensitive monitor of clonal expansion and contraction of cell populations in response to tumor growth or treatment.

The immune system has the innate ability to recognize mutations in tumor cells and protect the host from cancer progression via activation of a T cell response against tumor-specific antigens. While the immune system routinely eliminates potential tumors originating from the host, cancer can only be successfully established when the tumor cell manages to evade the immune response. Therefore aggressive research has been aimed at understanding the complex interactions between tumors and the immune system, which may lead to improved forms of cancer treatment. Guided by the wealth of new information that genomic methods provide, manipulation of the immune response has resulted in promising therapies by boosting the ability of the immune system to target cancer, or by limiting the ability of tumors to evade the natural immune response. Further advances in NGS technology have increased knowledge of the intricate pathways that regulate the immune response, and improved methods used to identify tumors that are appropriate candidates for specific immunological therapies. This application spotlight highlights recent advances in the immuno-oncology field, including evolving trends, needs of researchers, and genomic technologies that are available to aid in this rapidly advancing field. Three promising fields of immunotherapy are reviewed here, including checkpoint inhibitors, vaccine immunotherapy, and adoptive cell transfer.

• Checkpoint Inhibitors

The immune system has an elaborate network of mechanisms to recognize foreign pathogens or mutated epitopes that tumor cells present. Efforts made over the past decades have informed the current understanding about immune cell-intrinsic checkpoints that can prevent T cell activation. These are commonly used by tumors to evade the immune response. Manipulation of these checkpoints has shown great promise in recent therapeutic approaches. One key checkpoint occurs during T cell priming by antigen presenting cells, which requires costimulatory binding of the B7 ligand. Binding of B7 by the CTLA-4 receptor results in suppression of the T cell response . In 2011, the FDA approved a monoclonal antibody against this receptor (ipilimumab) for clinical use in metastatic melanoma. Another key checkpoint is the binding of PD1 to PDL1, for which 2 anti-PD1 antibodies (pembrolizumab and nivolumab) were approved in 2014 , and more inhibitory drugs are under development. Both of these therapies have shown good clinical responses a portion of the time. However, relatively few tumors have endogenous T cell responses that can respond to immune checkpoint blockade.

• Vaccine Immunotherapy

Mutations occurring in protein coding genes of cancer cells are a source of potential new antigens (neoantigens) that the immune system may target. To boost tissue-specific T cell immunity, vaccines have been explored since the 1980s. Limited success of early attempts in this field was possibly due, in part, to the presentation of antigens as whole cell lysates, in which highly effective immunogens were diluted with immunologically irrelevant antigens. Recent advances in NGS have enabled the predictive selection of neoantigens that are likely to elicit a tumor-specific response. A quality versus quantity approach is now showing promise. Characterization of the DNA and/or RNA of cancer cells is efficiently done by exome sequencing or transcriptome sequencing, focusing on mutations that are likely to be presented to immune cells. Neoantigen selection is facilitated by improved bioinformatics tools to analyze specific mutation profiles.  Computer algorithm-guided epitope prediction models enable intelligent selection of mutations likely to result in high-affinity epitopes that bind to MHC molecules.  Further advances in recombinant DNA technology, such as the transduction of neoantigen expressing RNAs into antigen presenting cells, have led to success in triggering tumor-specific immune responses. Recent successes in clinical trials, facilitated by rapid turnaround time for tumor analysis and vaccine development, indicate a possible increase in the use of these types of therapies

• Adaptive Cell Transfer

Adoptive cell transfer (ACT) therapy involves selection of tumor-specific lymphocytes. Similarly to vaccine development, neoantigen selection may be done prior to the screening or engineering of lymphocytes . Trials in ACT have been successful for targeting melanoma and certain leukemias, and are currently being applied to other types of cancers.

• CAR T-Cells

T lymphocytes can be modified ex vivo to express a chimeric antigen receptor (CAR) directed at tumor-specific antigens. The modified CAR T-cells are then injected back into the patient for in vivo targeting of tumors that served as the original source of the antigen. This method has led to several reports of infused CAR T-cells expanding 1000-fold, indicating an antigen-specific response. Furthermore, these methods led to positive clinical outcomes, with persistent CAR expression, and evidence of persistence of immunologic memory cells.

• Tumor Infiltrating Lymphocytes (TILs)

Characterization of tumor exomes has facilitated the discovery that tumor infiltrating lymphocytes (TILs) can recognize and target products of cancer mutations. When grown and activated in vitro, TILs can be screened prior to reinjection into patients, leading to active tumor targeting. Treatment of melanomas has yielded the best results, though further screening has identified the existence of TILs that can recognize neoantigens in other types of tumors.

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