Chimeric CD40 Proteins Enhance T Cell Cytotoxicity

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Solution Overview

Problem

Current immunotherapy approaches, such as agonistic antibodies targeting CD40, have shown low clinical responses in cancer patients despite activating antigen-presenting cells and promoting antitumor immunity.

Innovation Solution

Modified T cells expressing ectopic or chimeric CD40 proteins, which include a CD40 extracellular domain combined with a heterologous intracellular domain, are developed to enhance T-cell responses against cancer cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If agonistic antibodies targeting CD40 are used to activate APCs, then antitumor immunity is promoted, but clinical response remains low

Engineering Contradiction:

Improveclinical responseVSAvoidtherapeutic efficacy

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

Instead of activating APCs through CD40 on their surface (conventional approach), the invention inverts the strategy by expressing CD40 on T cells, allowing T cells to directly engage with CD40L on APCs. This role reversal enables T cells to actively stimulate APCs rather than passively responding to their activation, thereby improving therapeutic efficacy and clinical response.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The invention uses chimeric CD40 proteins as intermediaries that combine the extracellular domain of CD40 with heterologous intracellular signaling domains from other receptors (e.g., CD28, 4-1BB, OX40). These chimeric proteins mediate enhanced signaling when CD40 on T cells engages with CD40L on APCs, thereby improving the reliability and efficacy of antitumor immunity activation.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If T cells are modified to express ectopic CD40 protein, then T-cell responses against cancer cells are enhanced, but device complexity increases

Engineering Contradiction:

ImproveT-cell response efficacyVSAvoidcell modification complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention modifies the biochemical parameters of T cells by introducing chimeric CD40 proteins with altered intracellular domains. These parameter changes in protein structure and signaling capability enhance T-cell response efficacy without requiring complex structural modifications to the T cell itself, thereby improving reliability while managing complexity.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20250073268A1Chimeric CD40 polypeptides and methods of use in immunotherapy

Publication Date: 2025.03.06 PROVIDENCE HEALTH SYST OREGON

AI summary

Modified T cells comprising ectopic CD40 proteins (such as chimeric CD40 proteins including a CD40 extracellular domain and a heterologous intracellular domain) are provided. Also provided are compositions, including pharmaceutical formulations, comprising the modified T cells, and methods for increasing T cell-mediated tumor cell-specific cytotoxicity using the same. Methods of treating a subject with cancer including administering to the subject the modified T cells, thereby activating an innate immune response and/or an adaptive immune response in the subject are also provided.