Description:
CD4+ T cell markers, compositions, and methods for cancer therapy
Markers, methods, and compositions for identifying CD4+ T cells (or T cell receptor genes thereof) with tumor antigen specificity, tumor neoantigen specificity, and/or tumor-infiltrating capacity.
While cancer immunotherapies have historically focused on CD8+ T cells, tumor antigen specific CD4+ T cells are required for the efficacy of immune checkpoint inhibitors in murine models and there is growing support for their importance in treating human cancers with immunotherapy. Researchers at Fred Hutchinson Cancer Center have discovered a set of markers that characterize tumor reactive CD4+ T cells and subpopulations thereof in solid tumor samples. The researchers also found a significant correlation between the presence of these cells and overall survival in a cohort of melanoma patients. In addition to uses for prognosis, the identification of markers for these cell populations enables a variety of significant therapeutic applications. For example, these CD4+ T cells can be selected for prior to TCR sequencing to identify TCRs specific for tumor neoantigens or tumor associated antigens, which are then used to develop TCR therapies. Alternatively, these cells may be enriched for and/or expanded and used directly in a polyclonal CD4+ T cell therapy.
<ul>
<li>Markers can help detect and selectively expand CD4+ T cells with neoantigen specificity and/or tumor infiltrating capacity</li>
<li>CD4+ T cells expressing a TCR specific for a tumor neoantigen or tumor antigen can be used in a T cell (e.g., polyclonal) therapy</li>
<li>TCRs from tumor infiltrating CD4+ T cells may be sequenced, and the sequence information can inform other therapies (e.g., engineered TCR or CARs expressing antigen binding domain derived from these CD4+ neoantigen expressing cells); or soluble molecules comprising of binding domain from such a TCR or engineered TCR</li>
</ul>
<ul>
<li>The disclosed markers permit selecting for CD4+ T cells of interest and against bystander cells, improving the ability to enrich (from about 2-fold to about 20-fold better than conventional TIL culture methods), maintain, and expand these cells of interest</li>
<li>CD4+ T cells in the tumor are prognostic, since they correlated with the transcriptional states of CD8+ T cells and macrophages, maturation of B cells, patient survival and modification of tumor microenvironment (e.g., CXCL13+ CD4+ T cells in melanoma and breast cancer)</li>
</ul>
The global adoptive cell therapy market was estimated to be valued over $3 B in 2022 and is expected to grow rapidly in the next decide (at a CAGR of >20% over a 10-year period). CD4+ T cells that can be identified by this signature can be found across a number of common solid tumor types
<ul>
<li> Joshua Veatch, M.D., Ph.D.; Assistant Professor - Translational Science and Therapeutics Division</li>
<li> Stanley Riddell M.D.; Professor - Translational Science and Therapeutics Division; Member - Translational Data Science Integrated Research Center (TDS IRC); Burke O’Reilly Family Endowed Chair in Immunotherapy</li>
</ul>
Preclinical <em>in vitro</em>, Preclinical <em>in vivo</em>
WO2023164439A2, patent pending
21-188_Veatch_Neoantigen specific CD4 T cell_NCS_FHCC.pdf
TCR| neoantigen | TIL | tumor microenvironment | immune checkpoint inhibitor | MHC II | CD4+ | CXCL13 | melanoma | CAR |
Neoantigen-CD4-T-cell- 21-188