1021P - Chemotherapy and hypomethylating agents enhance anti-tumor activity of PRAME ImmTAC

Background

Immune-mobilizing monoclonal T cell receptor Against Cancer (ImmTAC) molecules are TCR-CD3 T cell engagers that redirect polyclonal T cells to kill tumors by binding to tumor peptides presented by HLA-A. ImmTAC that targets the cancer testis antigen (CTA) PRAME is in investigational clinical trials as monotherapy and in combination with chemotherapies in advanced solid tumors including melanoma, ovarian, endometrial, and lung (NCT04262466, NCT06112314). This study aims to evaluate whether combining PRAME ImmTAC with chemotherapy or a hypomethylating agent (HMA) enhances tumor cell killing in vitro.

Methods

PRAME ImmTAC-mediated T cell activation and killing of cell lines from lung, ovarian, and endometrial cancers was assessed in vitro with or without decitabine (dec), gemcitabine (gem), doxorubicin (dox), paclitaxel (pac), or carboplatin (carb). PRAME and antigen presentation machinery (APM) genes and proteins (HLA-A, B2M) were quantified by RT-qPCR and flow cytometry.

Results

Dec, an HMA known to increase CTA expression, resulted in up to 4-fold upregulation of PRAME transcripts in lung tumor cell lines. Dec also upregulated APM genes and surface expression in OVCAR3 cells, an ovarian cell line with low HLA-A2 expression. Gem up-regulated HLA-A2 surface expression up to 2-fold in multiple tumor lines. PRAME ImmTAC combination with dec or gem resulted in improved T cell-mediated IFNγ release (up to 3-fold increase in Emax) and tumor killing (up to 2-fold increase), particularly against tumors with low PRAME or APM expression. PRAME ImmTAC combination with either dox, pac, or pac+carb resulted in enhanced tumor cell killing, even at low effector: target (1:1) ratios (up 4-fold increase). The mechanisms by which these chemotherapies enhance PRAME ImmTAC-mediated tumor cell killing is under investigation.

Conclusions

Decitabine increased PRAME and APM, whilst gemcitabine increased APM expression in tumor cells. PRAME ImmTAC-mediated killing of ovarian, endometrial, and lung cell lines was enhanced when combined with dec, gem, dox, pac, pac+carb, with pac exhibiting the highest enhancement. These findings support combining PRAME ImmTAC with HMA or chemotherapy to enhance clinical efficacy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Immunocore Ltd.

Funding

Immunocore Ltd.

Disclosure

A. Benlahrech, J. Clubley, C. Britton-Rivet, A. Raczka, P.B. Kirk, S. Varadarajan: Financial Interests, Personal, Full or part-time Employment: Immunocore Ltd.