Promising New Targets for Cancer Vaccines Identified (2021)

cancer vaccine: cancer vaccineOver the past decade, scientists have been exploring therapeutic cancer vaccines. Experimental therapeutic cancer vaccines have the benefit of prompting specific immune responses to tumor antigens. Although vaccines against melanoma and non-small cell lung cancer show promise in clinical trials, significant obstacles still remain to their success. Cancer cells display unique mutated proteins called neoantigens on their surfaces. Choice of target antigen is of utmost importance when considering vaccine design. Fragments of certain neoantigens when injected into the body can alert the body's immune system to activate T cells to annihilate the cancerous cells. Although previous studies have shown that numerous neoantigens are found in most tumors, only a small number mount a T-cell response (Front Immunol 2021; https://doi.org/10.3389/fimmu.2021.672356). A new study, published in the journal Cell, took a closer look at the interplay of different populations of T cells marked by the transmembrane protein CD8, and how this interplay affects T-cell function and tumor control (2021; https://doi.org/10.1016/j.cell.2021.08.020). Burger and colleagues reveal how vaccination against certain neoantigens can boost overall T-cell response and help shrink tumors in mice. In a genetically engineered mouse model of lung cancer, the researchers discovered that immune dominance and rapid expansion are established in tumors that focus CD8 T-cell expansion on the antigen that most stably binds the major histocompatibility complex. Interestingly, these T cells experience a phenomenon known as T-cell exhaustion, which occurs when this dominant set of T cells no longer attacks tumor cells, and instead remains near the tumor creating an immunosuppressive environment which disables populations of T cells, allowing the tumor to grow unchecked. The scientists demonstrated T cells that respond to subdominant neoantigens express TCF1+ CD8 T cells—a transcription factor that plays an important role in T-cell development and differentiation—and is thought to underlie immune checkpoint blockade (ICB) therapy response. However, the subdominant T-cell response did not preferentially benefit from ICB due to a dysfunctional subset of TCF1+ CD8 T cells marked by expression of CCR6 and differentiation to poorly cytotoxic Tc17 cells. The scientists analyzed human samples and sequencing datasets to demonstrate that CCR6+ TCF1+ cells exist across human cancers and do not respond to immune checkpoint blockade. Upon vaccinating mice with such suppressed neoantigens, CCR6+ TCF1+ cells were eliminated and the subdominant response was dramatically improved response—the tumors in the animals shrank by an average of 27 percent as a result. Megan Burger, PhD, a postdoctoral fellow at MIT and lead author of the new study, added her perspectives. She is a T-cell immunologist and cancer biologist investigating mechanisms of T-cell dysfunction in tumors with the goal of identifying new targets for cancer immunotherapies. Oncology Times: How are cancer vaccines different from the vaccines that work against viruses? Burger: “The biggest difference is that vaccines for viruses are designed to prevent disease, while those targeting cancer are designed to treat disease. Otherwise, there is substantial overlap in the overall approach. Like vaccines against viruses, cancer vaccines generate an immune response against proteins specific to the cancer cells. One cancer vaccine approach being trialed delivers RNA that will encode for a target protein, similar to the way the SARS-CoV-2 vaccine works.” Oncology Times: Over the past decade, scientists have been exploring vaccination to help combat cancer. However, no such cancer vaccines have yet gained FDA approval. What have been the challenges? Burger: “The last generation of vaccines were designed to target cancer proteins that are shared across patients and even different cancer types. This would really have been a dream to create a vaccine that would work for all patients. However, these cancer proteins are also present in normal cells at some level, and hence our immune systems are educated to ignore them to prevent autoimmune disease. For this reason, vaccines against these proteins did not generate a very strong immune response against tumors. “With recent advances in genome sequencing technologies, we can now identify genetic mutations in patient tumors that give rise to proteins that are truly specific to the cancer, termed neoantigens. Mutations that give rise to neoantigens differ between patients and, hence, vaccine design must be personalized to each patient. While this would have previously presented an insurmountable barrier in terms of the time and cost associated with development of such a vaccine, new technologies have now made this a feasible approach and some of the early clinical trial results are very promising.” Oncology Times: What are potential clinical impacts of this study? Burger: “While personalized neoantigen vaccines have generated impressive results in clinical trials against melanoma, they have more limited efficacy across other cancer types. Our study provides new insight into the types of neoantigens we might want to target to achieve better responses. T-cell responses against certain neoantigens in tumors appear to be naturally suppressed but are sitting there with unrealized response potential. Targeting these neoantigens with vaccines can unleash these suppressed responses, resulting in greater tumor control.” Oncology Times: Are there plans to combine your cancer vaccine strategy with other substances to help boost the immune response even further? Burger: “Our findings indicate that there may be synergy between our vaccine approach and immune checkpoint blockade therapies like anti-PD-1/PD-L1 and anti-CTLA-4. This is something we are actively testing in the lab. Encouragingly, there is already evidence of potential synergy between personalized neoantigen vaccines and immune checkpoint blockade therapies from recent clinical trials. It would be exciting if our approach of targeting neoantigens associated with suppressed T-cell responses might result in even greater synergy.” Dibash Kumar Das is a contributing writer.