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Mechanisms of Response and Resistance to PSMA×CD3 Bispecifics in CD34+ Humanized Mice
Bethany K Mattson Cypert1, Krista Menard1, Gerald Chu1
1Janssen Research and Development, Spring House, Pennsylvania.
Abstract:
Prostate cancer is considered immunologically "cold," with low mutational burden, tumor-infiltrating immune cells, and PD-L1 levels, culminating in poor response to immune checkpoint therapies. CD3 bispecific redirection antibodies can elicit T cell-mediated cytotoxicity and hold promise for immune cell recruitment into prostate tumors. CD3 redirection antibodies in solid tumors are still in the early phases of clinical development, and it is not yet understood whether these potential therapies will achieve the high response rates observed in hematologic malignancies or result in durable T-cell responses. In this study, we demonstrated that treatment with a prostate-specific membrane antigen (PSMA)-targeted CD3 redirector resulted in efficacy against LnCaP.AR human prostate xenografts in CD34+ cord blood-humanized mice. Efficacy correlated with T-cell infiltration into tumors with an activated phenotype and also increased PD-L1 expression. Engineered overexpression of PD-L1 in LNCaP.AR tumors resulted in resistance to PSMA×CD3 bispecific antibody treatment, whereas sensitivity was restored in combination with anti-PD-1 antibody pembrolizumab. PSMA×CD3 and anti-PD-1 combination treatment resulted in complete tumor responses in approximately 20% of mice and elicited immune responses that delayed growth of rechallenged tumors. In a second prostate model, patient-derived LuCaP 86.2 xenografts, PSMA×CD3 monotherapy treatment resulted in complete responses in 25% of mice. When PSMA×CD3-treated responder mice were rechallenged with LuCaP 86.2 tumors, partial control of tumor regrowth was associated with the expansion of effector memory T cells. These studies show that PSMA×CD3 treatment elicits antitumor memory T-cell responses and that combination with PD-1 blockade can enhance these effects in tumors with immune-suppressive tumor microenvironments.
Insights
Prostate cancer, often resistant to immunotherapy, shows promise with PSMA×CD3 bispecific antibodies. Combining this with PD-1 blockade enhances T-cell responses and leads to durable tumor control, even in challenging models.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Prostate cancer is immunologically "cold," limiting response to current immunotherapies.
- CD3 bispecific antibodies can redirect T cells to kill cancer cells, offering a new therapeutic avenue.
- The efficacy and durability of CD3 redirection antibodies in solid tumors, like prostate cancer, require further investigation.
Purpose of the Study:
- To evaluate the efficacy of a prostate-specific membrane antigen (PSMA)-targeted CD3 bispecific antibody in preclinical prostate cancer models.
- To investigate the role of PD-L1 expression in response to PSMA×CD3 therapy.
- To assess the potential of combining PSMA×CD3 therapy with PD-1 blockade for enhanced antitumor immunity.
Main Methods:
- Treatment of human prostate cancer xenografts (LnCaP.AR and LuCaP 86.2) in humanized mice with PSMA×CD3 bispecific antibody.
- Assessment of tumor growth, T-cell infiltration, phenotype, and PD-L1 expression.
- Combination therapy studies involving PSMA×CD3 and anti-PD-1 (pembrolizumab).
- Tumor rechallenge experiments to evaluate immune memory.
Main Results:
- PSMA×CD3 treatment demonstrated efficacy against prostate cancer xenografts, correlating with increased T-cell infiltration and activation.
- Engineered PD-L1 overexpression conferred resistance to PSMA×CD3, which was reversed by combination with anti-PD-1 therapy.
- Combination therapy achieved complete tumor responses in 20% of mice and induced immune memory.
- PSMA×CD3 monotherapy achieved complete responses in 25% of mice with patient-derived xenografts, and rechallenge studies indicated partial tumor control associated with effector memory T cells.
Conclusions:
- PSMA×CD3 bispecific antibody therapy can elicit T-cell-mediated antitumor responses in prostate cancer models.
- Combination with PD-1 blockade can overcome immune suppression and enhance therapeutic efficacy and durability.
- PSMA×CD3 treatment can induce antitumor T-cell memory responses, suggesting potential for long-term benefit.
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