Polyclonal anti-tumor immunity by engineered human T cells

Introduction

Adoptive T cell therapies are a new class of living drugs, achieving durable results in a subset of patients with aggressive malignancies. These transformative outcomes are not shared with the majority of patients with solid tumors that remain resistant to current T cell therapies.

Challenges in Current Therapies

As engineered T cell therapy is usually directed against a single antigen, it is especially vulnerable to antigen loss as a tumor resistance mechanism. Moreover, cancer immunotherapy often leads to severe immune-related adverse events (irAE) by destructive self-reactivity that must be evaluated together with the therapeutic benefit.

While T cell therapies with tumor-infiltrating lymphocytes might circumvent these shortcomings, tumor tissue availability is limited and T cells are poorly responsive to ex-vivo perturbation. These therapeutic challenges highlight the gaps in our knowledge of how to engineer curative anti-tumor immunity.

Recent Developments

We recently developed foundational platforms for:

1. CRISPR engineering
2. TCR repertoire manipulation
3. Single-cell omics of primary human T cells

We plan to leverage these opportune achievements to address the critical gaps in adoptive T cell therapies.

Focus Areas

We will focus on three important aspects of engineered anti-tumor immunity:

1. Efficacy: We will tune TCR sensitivity by perturbing key genes to determine how TCR signaling balances burst-like effector function and long-term persistence.
2. Safety: We will reveal the sequestered self-reactive T cell compartment to control for irAE following immunotherapy.
3. Specificity: We will directly uncouple anti-tumor TCR repertoires from their dysfunctional state to mount a polyclonal anti-tumor immune response.

Innovative Strategy

This strategy is radically different from current T cell therapies as it is agnostic to specific tumor antigens and leverages pre-existing polyclonal antitumor immunity. These studies will chart novel blueprints for robust, safe, and specific engineered cell therapies targeting solid tumors.