Innovative Approach to Drive Progress

Elucidating the mechanisms that regulate various immune cell subsets — such as NK cells, dendritic cells and myeloid cells — in order to expand our knowledge on how these cells function and how they can be targeted to improve anti-tumor immune responses

• T cell biology: T cells are the front line of the immune system’s fight against cancer, recognizing aberrant tumor antigens and killing cancer cells. James P. Allison, Ph.D., discovered that CTLA-4 is an immune checkpoint that turns off the T cell response and that inhibiting CTLA-4 can ignite an anti-tumor response, marking the rise of modern cancer immunotherapy. Today, researchers at the Allison Institute continue to uncover new aspects of the T cell life cycle, aiming to discover innovative ways to combat cancer.
• Myeloid cell biology: Myeloid cells, which include macrophages, dendritic cells and many other cell types, are a key component of the innate immune system and play crucial roles in the tumor immune response. Dendritic cells phagocytize dead cancer cells and cross-present tumor antigens to activate T cells. In contrast, macrophages in the tumor microenvironment often adopt an inhibitory cell fate, blocking T cell entry into the tumor. Allison Institute investigators are researching many aspects of myeloid cell biology, seeking breakthroughs that could tip the scales toward tumor rejection when combined with existing immunotherapies.
• NK cell biology: Natural killer (NK) cells are a vital part of the innate immune system, known for their ability to target and destroy tumor cells without prior sensitization. They directly kill cancer cells by releasing cytotoxic granules containing perforin and granzymes, inducing apoptosis. NK cells also secrete cytokines like interferon-gamma (IFN-γ) to boost the anti-tumor activity of other immune cells. Additionally, they can detect and eliminate cancer cells that have downregulated MHC class I molecules, a common evasion tactic. Enhancing NK cell function and persistence is being explored as a promising approach in cancer immunotherapy.
• B cell biology: B cells, a crucial component of the adaptive immune system, contribute to the tumor immune response through antibody production, antigen presentation and cytokine secretion. They produce antibodies that can target and neutralize tumor cells, facilitate their phagocytosis and present tumor antigens to T cells, thus bridging innate and adaptive immunity. B cells also play a role in forming tertiary lymphoid structures (TLS) within tumors, which are organized aggregates of immune cells. The presence of TLS has been correlated with improved responses to immunotherapy, as these structures can enhance local immune activation and promote effective anti-tumor responses. Researchers are investigating ways to leverage B cells and TLS to improve cancer treatment outcomes.
• Epigenetics: Epigenetic modifications, such as DNA methylation and histone modification, influence the differentiation and activity of immune cells involved in the tumor immune response, often permanently. Tumors often thrive under these immunosuppressive conditions. Blocking these epigenetic modifications can reactivate anti-tumor immune functions, enhancing the immune response against cancer. Consequently, Allison Institute investigators are actively exploring epigenetic therapies as promising strategies to improve cancer immunotherapy outcomes.
• Microbiome: The microbiome, the community of microorganisms living in the body, plays a crucial role in shaping the tumor immune response and influencing patients’ responses to immune checkpoint blockade. Certain gut bacteria can enhance the effectiveness of immunotherapies by modulating the immune system’s activity. A diverse and healthy microbiome can improve the body’s ability to mount an effective anti-tumor response, while dysbiosis, or an imbalance in the microbial community, can impair this process. Groundbreaking work by Allison Institute researchers has highlighted the potential of manipulating the microbiome to boost the efficacy of immune checkpoint inhibitors, offering new avenues for cancer treatment.
• Cancer neoantigens: Cancer neoantigens are novel protein fragments that arise from mutations unique to tumor cells, making them distinct from normal cellular proteins. These neoantigens can be recognized by the immune system as foreign, triggering a targeted anti-tumor immune response. Research into neoantigens is crucial because it can lead to the development of personalized immunotherapies, such as neoantigen-based vaccines and adoptive T cell therapies.

Testing novel combination strategies in patients, with a focus on understanding how the immune system and tumor microenvironment respond and how these responses correlate with clinical outcomes

• Rational combinatorial immune checkpoint blockade trials: Recent clinical trials have shown that combination immunotherapies are a promising path to enhancing the efficacy of existing treatments. However, the rapid increase in combination trials has outpaced the fundamental understanding of how these immunotherapies work as single agents or in combination. This gap highlights the need for concerted efforts to uncover the immunological mechanisms underlying the response to individual drugs. By deepening our knowledge of these mechanisms, Allison Institute researchers are designing more effective and rational combination therapies, ultimately improving patient outcomes and advancing cancer treatment.
• Iterative translation (clinic to bench): There are no failed clinical trials as long as lessons are learned that improve the next trial. Through its first-of-its-kind Immunotherapy Platform, the Allison Institute profiles changes in the tumor and other tissues that occur during the course of immunotherapy. Lessons learned through immune profiling fuel discovery research into the biological mechanisms behind the response. This comprehensive approach ensures that each trial, regardless of its immediate outcome, contributes valuable insights that drive the development of more effective cancer treatments. The cycle is completed when the insights lead to new therapeutic regimens for cancer patients.

Spatial profiling technologies have revolutionized cancer immunology research by enabling the precise mapping of cellular interactions within the tumor microenvironment. These advanced methods allow scientists to visualize the spatial distribution of immune cells, stromal cells and tumor cells, offering insights into the complex cellular networks that drive cancer progression and immune responses. The benefits of spatial profiling include enhanced understanding of tumor heterogeneity, identification of novel biomarkers, and the ability to assess the spatial context of immune cell infiltration. To extract maximum value from these complex data sets, new data science approaches are essential, enabling the integration and analysis of vast amounts of spatial and molecular information. Allison Institute researchers are pushing the boundaries of spatial profiling to get maximum information from tumor samples.

Exploring opportunities to leverage the immune system to intercept cancer at its earliest stages

• Cancer vaccines: Vaccines have emerged as a promising strategy to prevent certain types of cancer. The most notable example is the HPV vaccine, which has significantly reduced the incidence of cervical cancer and other HPV-related cancers. Additionally, the hepatitis B vaccine has been effective in lowering the risk of liver cancer. Looking to the future, researchers are exploring the potential of personalized cancer vaccines, which aim to stimulate the immune system to target specific tumor antigens unique to an individual’s cancer.