MHC class II restricted T cell receptors targeting mutations in EGFR

Description:

Compositions and methods for targeting EGFR antigens (for e.g., to treat or manage cancer)

Activating mutations in EGFR cause a subset of non-small cell lung cancer that occurs preferentially in women and non-smokers. EGFR mutated lung cancer responds to small molecule kinase inhibitors, but resistance occurs in almost all cases, and they do not benefit from existing immune therapies, so new immune therapies are necessary. While CAR and TCR immunotherapies have historically focused on CD8+ T cells, there is growing support for the importance of CD4+ cells in driving effective immunotherapy, including recent reports of clinical success with MAGE-A3 TCR CD4+ adoptive cell therapy. Here, Fred Hutchinson Cancer Center researchers have discovered MHC class 2 directed T cell receptors that specifically recognize 2 different recurrent EGFR mutations that could be used for novel CD4+ T cell therapies to target patients with these EGFR mutations.

<ul>
   <li>Adoptive CD4+ T cell transfer with transgenic TCRs to be used as immunotherapy in subjects having or at risk for a cancer with mutant EGFR expression or activity</li>
   <li>Combination treatment with anti-PD 1 </li>
</ul>

<ul>
   <li>Novel treatment strategy for targeting difficult to treat disease or disorder associated with EGFR expression or activity that are not responsive to ICI treatment</li>
   <li>Can be applied to solid tumors and hematologic malignancies</li>
   <li>Presentation by HLA obviates need for high cell surface expression</li>
   <li>Tumor antigen specific CD4+ T cells correlate with an activated tumor immune microenvironment allowing for better therapeutic activity of engineered cells and synergy with other immune therapies (immune checkpoint inhibitors, adoptive cell therapy with CD8+ T cells etc.)<li>
</ul>

Immune checkpoint inhibitors (ICI) have transformed treatment of non-small cell lung cancer (NSCLC) and multiple other cancers, though many patients do not benefit or develop resistance to ICI. Patients with EGFR mutations respond to EGFR inhibitors such as osimertinib, but resistance inevitably occurs. Thus, new treatment options for patients resistant to EGFR inhibitors and non-responsive to ICI are needed. In 2021, sales of NSCLC drugs totaled US $24.1 billion across the major markets, of which EGFR-targeted therapies amassed $3.9 billion. EGFR L858R and Exon 19 Del mutations occur frequently (~30% and > 45% respectively) in NSCLC; though the TCR targeting these mutations and having the matching HLA type can account for about 6% of the NSCLC patients.

<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>

PCT application. Patent pending

22-111_Veatch_Immunotherapy targeting EGFR Ag_FHCC.pdf

Immunotherapy-targeting-EGFR-Ag-22-111