Immunotherapies and Mechanisms of Immune Escape

Chaired By

 Esra Akbay, PhD of UT Southwestern Medical Center
 Monica Guzman, PhD of Weill Cornell Medicine

Meeting Description

Modern immunotherapy concepts have changed cancer treatment paradigms, such as immune checkpoint blockade, chimeric antigen receptor (CAR) T cells, and antibody-based therapies have made rapid progress in the past 10 years and are currently used to treat many cancers. Immune checkpoint inhibition circumvents tumor-induced suppression of cytotoxic T cell function. Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) are currently approved treat CD19-positive cancers. However, only a fraction of patients responds, especially in the field of solid tumors as, for example, the immune microenvironment plays a critical role in disease progression and outcomes as it can induce immune suppressive signals that prevent immune-surveillance and allow malignant cells to persist. Therefore, combination treatments using different kind of immunotherapies targeting multiple checkpoints are necessary for more effective responses. Discussing all the components that are known to play a role in the mechanisms of immune escape and the emerging concepts for therapeutic interventions in a multidisciplinary setting will lead to the implementation of rationally designed trials to better harness immune system for the benefit of cancer patients.

Meeting Summary

The forum was set to discuss the role of the tumor microenvironment in preventing immunotherapies from eliminating tumors. Novel concepts such as bioengineering models, delivery systems, the genetic and epigenetic make up, identification of new targets, and combinatorial therapies were also discussed. The participants were from diverse disciplines which allowed for cross fertilization of ideas and will likely result in new innovative collaborations.

The Forum was divided into 4 sections, structured to (1) discuss challenges that have hampered the success of antigen receptor (CAR) T targets and immune checkpoint inhibitors in solid and liquid tumors; (2) present innovative technologies that can help overcome some challenges evaluating or implementing immune therapies; (3) evaluate the components of the tumor microenvironment or other factors that may contribute to resistance to immune therapies; (4) propose alternative therapeutic approaches to improve upon immune therapies.

Briefly, Fabiana Perna talked about challenges when selecting chimeric antigen receptor (CAR) T targets as often may have toxicity against normal tissues, she discussed a novel platform for the discovery of novel CART targets using unbiased proteomic approaches. Andrei Thomas-Tikhonenko covered the mechanism that result in escape of tumors cells to CAR T cells in leukemia which involve splicing changes that result in the lack of the expression of the antigen on the cell surface of the cells. Such changes also affect response to antibody drug conjugate therapies by the loss of antibody target antigens through splicing alterations.

Esra Akbay talked about the relevance of tumor mutational burden (TMB) as a biomarker for sensitivity checkpoint blockade therapy and potential implementation of novel mouse models and their limitations.

Ankur Singh presented innovative hydrogel models and bioreactors to evaluate 3D structures such as tumor organoids. This opened an interest for the potential integration of immune cells into these systems to mimic the tumor microenvironment to better understand and address mechanisms of resistance. Jinming Gao talked about the nanotechnology tools to examine pH in tumors in vivo models and human clinical trials. This approach allows for improved visualization of the tumors for resection. Furthermore, he discussed nanoparticle encapsulated cancer vaccine potentiating STING pathway (a key mediator of inflammation) locally. Michael Birnbaum presented his high throughput screen approach to test all potential combinations signaling domains to improve upon activity of CAR T cells.

David Raulet talked about stimulating NK cells by cyclic dinucleotides activating molecules to target CD8 T cell resistant tumors some of which lack antigens or do not present antigens. He also described a superkine IL2 approach that can overcome NK cell exhaustion. David DeNardo talked about how different tumor microenvironments (lung vs pancreas) have different immune context and different response to ICB. He showed that this was due to dendritic cell absence in pancreas. Lucy Godley lead a discussion around the impact of germline mutations that may affect the tumor microenvironment, in addition to pre-disposing events such as clonal hematopoiesis that also may impact the response of patients to immune therapies.

Lorenzo Galluzzi discussed a combinatorial approach of radiation therapy to improve CAR T cell therapies via a CAR independent interaction. Monica Guzman discussed the role of epichaperome inhibitors as a mechanism to improve immune responses in patients. Stephanie Dougan, dynamically presented how T cells can mediate resistance to immune checkpoint inhibitors.

Overall, all discussions were very dynamic and interactive. Several collaborations we discussed to for example: Improve delivery of inhibitors via nanoparticles, to implement novel bio engineered models to study the role of immune cells in tumor organoids, to anticipate mechanism of resistance in novel discovered CAR T targets evaluating splicing events.

Forum Participants