Towards an integrated understanding of immunotherapy resistance

There are few topics in the field of cancer immunotherapy that are currently more pertinent than resistance as the majority of cancers fail to respond to this treatment modality. Given the broadly recognized implications of understanding the underlying mechanisms of both primary (innate) and secondary (acquired) resistance in drug and biomarker development, this topic is of great interest to many different stakeholders in the field. Accordingly, this issue of Immuno-Oncology Insights addresses several important, yet less mainstream, aspects of the complex and rapidly moving area of immunotherapy resistance by turning its attention towards discussions regarding the resistance of solid tumors to the genetically-engineered T cell therapies. Further consideration is also given to other components of the Cancer Immunity Cycle beyond the T cell, with a focus on the dendritic cell (DC) as an important and generally overlooked node of immunotherapy resistance.

Multiple barriers to the generation of an effective anti-tumor immune response are recognized within the tumor microenvironment (TME). However, the complex interplay between the tumor and the host immune system remains poorly understood. A discussion with Dr Alfonso Quintás-Cardama (TCR² Therapeutics) highlights the impressive challenges faced by cytolytic T cells within the TME and what steps can be taken to overcome these barriers. In particular, this discussion provides an interesting overview of a T cell-based platform referred to as TRuCs, or T cell-receptor fusion Constructs, that his group is employing to boost responses to engineered T cells in solid tumors. This is accompanied by further dialogue with Dr Prasad Adusumilli of the Memorial Sloan-Kettering Cancer Center about his group’s priorities and approaches for the development of next-generation CAR T cells for overcoming resistance mechanisms in mesothelioma and other metastatic solid tumors. Serving as an excellent backdrop to these discussions, Dr Ingunn Stromnes of the University of Minnesota provides an overview of the current state of and future challenges faced by engineered T cell therapeutics in solid tumors. This includes a summary of TCR-engineered T cells and what measures can be taken to combat against resistance and tumor escape.

When examining the Cancer Immunity Cycle, it quickly becomes apparent, however, that other components of the host immune system are also critical for the generation of an effective anti-tumor immune response. Indeed, recent studies have delineated that the antigen cross-presenting Batf3⁺ type I DC is essential for the generation of both spontaneous anti-tumor immunity as well as effective tumor antigen-specific cytolytic T cell responses to checkpoint inhibitor immunotherapy. In an opinion piece written by Dr David Munn and colleagues at the Georgia Cancer Center, potential DC-specific targeting strategies are discussed for augmenting responses to the available checkpoint inhibitor therapies. Further insight is given to the development and relevance of dysfunctional DCs in the TME and how select strategies to target common pathways of DC tolerization may be a particularly powerful approach for overcoming immunotherapy resistance and improving clinical outcomes in solid tumor patients.

Finally, I-O Insights reports on a fascinating conversation with Dr Todd Golub of the Broad Institute explaining his view on how genomic approaches can be leveraged in the immuno-oncology space to interrogate resistance mechanisms and provide insight into the design of novel combination regimens. Dr Golub further underscores the importance of engineering improved model systems for investigating immunotherapy resistance and why this is an important step forward for developing the mechanistic understanding necessary for extending clinically relevant responses to a broader population of cancer patients. In addition, as underscored by Dr Adusumilli, improved correlative immunologic data from clinical trials will also be necessary to better understand the impact of therapeutic agents on the tumor immune microenvironment. Additional technologies such as single-cell RNA sequencing, spatial transcriptional profiling, and the implementation of various CRISPR/Cas9 genetic screens will also likely play important roles in contributing to a better understanding of immunotherapy resistance.

The complexities of the TME, as discussed here, coupled with intra- and inter-tumor heterogeneity as well as the important, but less studied, aspects of therapeutic sequencing create significant challenges for the future of solid tumor immunotherapy. However, an integrated approach taken by each of the stakeholders in immuno-oncology is poised to continue advancing the field towards a better understanding of the hidden secrets underlying tumor immunotherapy resistance. Further discussion and thoughtful debate as facilitated by Immuno-Oncology Insights is expected to play an important role in catalyzing this process.

Affiliation

Brent A Hanks
Associate Professor of Medical Oncology in the Department of Medicine and Assistant Professor in the Department of Pharmacology and Cancer Biology, Duke University

Authorship & Conflict of Interest

Contributions: All named authors take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Acknowledgements: None.

Disclosure and potential conflicts of interest: Dr Hanks reports grants and non-financial support from Merck; personal fees from Merck; grants and non-financial support from Tempest Therapeutics; grants and non-financial support from Leap Therapeutics; grants and non-financial support from A*STAR Singapore; grants from Sanofi, personal fees from G1 Therapeutics; grants and non-financial support from MedPacto, Inc; grants and non-financial support from OncoMed Therapeutics; grants and non-financial support from AstraZeneca. In addition, Dr Hanks has a patent Composition Of Matter And Methods For Alteration Of Dendritic Cell Metabolism To Augment Cancer Vaccine Efficacy, and two patents pending: Compositions And Methods For Increasing The Efficacy Of Anti-Pd-1 Antibody Immunotherapy, and Predictive Biomarkers For Cancer Immunotherapy And Methods Of Using Same.

Funding declaration: The author received no financial support for the research, authorship and/or publication of this article.

Article & copyright information

Copyright: Published by Cell and Gene Therapy Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Attribution: Copyright © 2021 Hanks BA. Published by Immuno-Oncology Insights under Creative Commons License Deed CC BY NC ND 4.0.

Article source: Invited.

Revised manuscript received: Feb 3 2021; Publication date: Feb 9 2021.