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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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APR-246 increases tumor antigenicity independent of p53

Judith Michels1,2, Divya Venkatesh1,2, Cailian Liu1,2

  • 1Department of Pharmacology, Swim Across America and Ludwig Collaborative Laboratory, Weill Cornell Medicine, New York, NY, USA.

Life Science Alliance
|October 27, 2023
PubMed

Insights

APR-246 enhances tumor cell immunogenicity, boosting T cell responses and vaccine efficacy, even in p53-deficient tumors. Combining APR-246 with immune agonists yields significant antitumor effects, offering a p53-independent therapeutic strategy.

Area of Science:

  • Oncology
  • Immunology
  • Drug Discovery

Background:

  • APR-246 previously showed potential in reprogramming tumor-associated macrophages to overcome resistance to immune checkpoint blockade.
  • The role of APR-246 and its active metabolite, methylene quinuclidinone (MQ), in directly enhancing tumor cell immunogenicity was investigated.

Purpose of the Study:

  • To determine if APR-246/MQ can directly increase tumor cell immunogenicity and enhance anti-tumor immune responses.
  • To explore novel combinations of APR-246 with immunomodulatory agents for improved anti-tumor efficacy.
  • To investigate the mechanism underlying MQ-induced immunogenicity.

Main Methods:

  • Treatment of murine B16F10 melanoma cells with APR-246/MQ.
  • Assessment of melanoma-specific CD8+ T cell activation.
  • Evaluation of tumor cell vaccine efficacy using MQ-treated cells.
  • Development and testing of a combination therapy including APR-246, a TLR-4 agonist, and a CD40 agonist.
  • Comparison of MQ effects with iodoacetamide, a cysteine-reactive compound.

Main Results:

  • MQ treatment enhanced tumor cell immunogenicity, promoting CD8+ T cell activation.
  • A tumor cell vaccine using MQ-treated cells demonstrated increased efficacy, independent of p53 status.
  • Combination therapy with APR-246, a TLR-4 agonist, and a CD40 agonist produced a significant anti-tumor response.
  • The immunogenic effects of MQ were linked to its thiol-reactive alkylating ability, similar to iodoacetamide.

Conclusions:

  • APR-246 and its active moiety MQ can directly enhance tumor cell immunogenicity, leading to improved T cell responses and vaccine efficacy.
  • Combination of APR-246 with immunomodulatory agents offers a promising p53-independent strategy for eliciting effective anti-tumor immune responses.

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