From understanding to rational design of next-generation cancer therapies

Introduction

Immunotherapy combined with cytotoxic and molecular therapies have entered centre stage as novel treatments for cancer. Despite this advance, toxicity and insufficient efficacy in many patients remain major obstacles and illustrate the need for therapy improvement based on a deeper understanding of the cellular damage and repair responses to drugs and immunotherapy.

Proposed Approach

To overcome this roadblock, I propose a previously unappreciated approach by combining immunotherapy with cancer therapies at ultra-low, sublethal doses. We demonstrated that cytotoxic T cells induce sublethal membrane and DNA damage and oxidative stress which, when repaired, allows for tumor cell survival. However, when damage adds up, the tumor cell dies.

Hypothesis

I hypothesize that sublethal effects reveal novel vulnerabilities in cancer cells which can be exploited by complementary multi-targeted therapies at ultra-low doses that are nontoxic individually but, when combined, achieve lethality by an additive mechanism.

Methodology

Taking advantage of innovative microscopy, I aim to produce a catalogue of damages and repair types, and their combined effects in tumor cells. Single-cell analyses combined with advanced statistics and mathematical modeling will be used to derive the damage profile and duration of damage for each modality in tumor cells, yet without side effects towards immune effector cells.

Algorithm Design

I will design algorithms for multi-targeted regimens to achieve additive damage, reduced repair, and death induction, and validate them in immunotherapy models in vitro and in local and disseminated preclinical cancer in vivo. If resistance occurs, survival programs will be detected by single-cell transcriptomics and countered by orthogonal targeting.

Objectives

subLETHAL will:

1. Identify sublethal damage as the basis of cytotoxic therapy.
2. Enable rational design of multi-targeted ultra-low dose additive regimens.
3. Advance the understanding, efficacy, and tolerability of chemoimmunotherapy.
4. Facilitate rapid clinical translation.