Unlocking a T cell-mediated Immune response in therapy-challenged Tumors

Introduction

Immuno- and targeted therapies have revolutionized the treatment of cancer patients, and more innovative therapeutics, such as KRAS inhibitors (KRASi), are entering the clinic. However, their use as monotherapies fails to achieve durable tumor control in most patients, and the development of combination therapies remains challenging without an understanding of the complex and dynamic biology that unfolds upon therapeutic challenge in the tumor microenvironment (TME).

Current Knowledge Gaps

Most of our knowledge on combination therapies is based on primary, treatment-naïve tumors. However, how signaling networks of cancer cells and their interactions with immune cells evolve under therapeutic challenge over time is poorly understood. Additionally, strategies to overcome immune-evasive TMEs are lacking.

Project Goals

Here, we build on our expertise in modeling the dynamic changes of cancer cells in all phases of therapy to move towards strategic, mechanism-based combination therapies. Our vision is to unlock a T cell-mediated immune response in therapy-challenged tumors, “UnlockIT”, to achieve durable therapy responses in cancer patients.

Methodology

1. Molecular Time Machine: We will use our improved molecular time machine, CaTCHseq, together with novel KRASi and unique KRAS-driven tumor models to understand tumor-TME co-evolution under KRASi and related mechanisms of drug resistance.

2. Characterization of Antigen Processing: We will characterize mediators of antigen processing and presentation in treatment-naïve, therapy-challenged, and immune-evasive cancer cell states by using state-of-the-art genome-wide CRISPR/Cas9 screens in combination with innovative phenotypic readouts. This approach offers a sought-after opportunity to uncover mechanisms that make cancer cells “visible” to immunity.

3. Targeting Antigen-Presenting Cells: Finally, we aim to overcome immune-evasive TMEs by understanding and targeting antigen-presenting cells in the TME.

Conclusion

Taken together, UnlockIT will provide new mechanistic links between oncogenic pathways and immunity, and thereby establish a rational basis for combining targeted and immunotherapies.