Abstract 12P
Background
mCRPC is an advanced disease stage where, regardless of testosterone-castration, the disease shows a more aggressive phenotype refractory to systemic treatment. STAR0602 is a novel anti-TCR Vb6 targeted antibody fused to IL-2 capable of inducing potent anti-tumor effect by expanding Vb CD8+ memory T cells. To date, STAR0602 is being evaluated in a phase 1/2 clinical trial (NCT05592626) for the treatment of advanced solid tumors and to assess safety and clinical activity. In the present study, we tested the hypothesis that the combination of mSTAR1302, the murine surrogate of STAR0602, with the PARPi Olaparib, will achieve a robust anti-tumor efficacy in a prostate cancer model.
Methods
Using TRAMP-C2 and RM-1, both syngeneic murine prostate cancer models classified as an immunologically “cold” tumors, we assessed anti-tumor activity and survival benefit after combination therapy. To determine the requirement of a subset of immune cells (NK cells, CD4+, CD8+, and Vb13 T cells) or the demand of IFNg for the therapeutic efficacy of combination therapy, depletion studies were performed. Finally, tumors were harvested for flow cytometry and RNA expression analyses.
Results
In vivo studies demonstrated that mSTAR1302 plus Olaparib combination therapy elicited a significant tumor suppression of TRAMP-C2 and RM-1 tumors compared to mSTAR1302 or Olaparib monotherapies. In the TRAMP-C2 tumor model, combination therapy resulted in survival benefit. Individual depletion of CD4+, CD8+, and Vb13+ T cells and NK cells and IFNg abrogated the ability of combination therapy in suppressing TRAMP-C2 tumor growth. Combination therapy significantly increased the percentage of CD4+ and CD8+ T cells recruited into the tumor together with an expansion of activated CD4+ Vb13 and CD8+ Vb13 T cells.
Conclusions
In summary, mSTAR1302 plus Olaparib combination therapy was shown to modulate the immune response, thereby achieving a robust anti-tumor effect. This data strongly supports the rationale for the design of clinical trials in mCRPC using combination therapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
NIH-National Institutes of Healths, Center for Cancer Research, CIO-Center for Immuno-Oncology.
Funding
Marengo Therapeutics.
Disclosure
A.I. Bayliffe: Financial Interests, Personal and Institutional, Ownership Interest: Marengo therapeutics. Z. Su: Financial Interests, Personal and Institutional, Stocks/Shares: Marengo therapeutics. J. Moisan, M. Katragadda: Financial Interests, Personal and Institutional, Full or part-time Employment: Marengo therapeutics. All other authors have declared no conflicts of interest.