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Enhancement of PSMA-Directed CAR Adoptive Immunotherapy by PD-1/PD-L1 Blockade
Inna Serganova1, Ekaterina Moroz1, Ivan Cohen2
1Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Abstract:
Chimeric antigen receptor (CAR) T cell therapy in hematologic malignancies has shown remarkable responses, but the same level of success has not been observed in solid tumors. A new prostate cancer model (Myc-CaP:PSMA(+)) and a second-generation anti-hPSMA human CAR T cells expressing a Click Beetle Red luciferase reporter) were used to study hPSMA targeting and assess CAR T cell trafficking and persistence by bioluminescence imaging (BLI). We investigated the antitumor efficacy of human CAR T cells targeting human prostate-specific membrane antigen (hPSMA), in the presence and absence of the target antigen; first alone and then combined with a monoclonal antibody targeting the human programmed death receptor 1 (anti-hPD1 mAb). PDL-1 expression was detected in Myc-CaP murine prostate tumors growing in immune competent FVB/N and immune-deficient SCID mice. Endogenous CD3+ T cells were restricted from the centers of Myc-CaP tumor nodules growing in FVB/N mice. Following anti-programmed cell death protein 1 (PD-1) treatment, the restriction of CD3+ T cells was reversed, and a tumor-treatment response was observed. Adoptive hPSMA-CAR T cell immunotherapy was enhanced when combined with PD-1 blockade, but the treatment response was of comparatively short duration, suggesting other immune modulation mechanisms exist and restrict CAR T cell targeting, function, and persistence in hPSMA expressing Myc-CaP tumors. Interestingly, an "inverse pattern" of CAR T cell BLI intensity was observed in control and test tumors, which suggests CAR T cells undergo changes leading to a loss of signal and/or number following hPSMA-specific activation. The lower BLI signal intensity in the hPSMA test tumors (compared with controls) is due in part to a decrease in T cell mitochondrial function following T cell activation, which may limit the intensity of the ATP-dependent Luciferin-luciferase bioluminescence signal.
Insights
Chimeric antigen receptor (CAR) T-cell therapy shows promise for prostate cancer, but solid tumor success lags. Combining CAR T-cells with PD-1 blockade enhances efficacy, yet persistence remains limited, suggesting further immune modulation is needed.
Area of Science:
- Immunotherapy
- Oncology
- Cellular Biology
Background:
- Chimeric antigen receptor (CAR) T-cell therapy has revolutionized hematologic malignancy treatment.
- Its efficacy in solid tumors, like prostate cancer, remains a significant challenge.
- Understanding immune evasion mechanisms is crucial for improving CAR T-cell therapy in solid tumors.
Purpose of the Study:
- To investigate the antitumor efficacy of human CAR T-cells targeting human prostate-specific membrane antigen (hPSMA) in a prostate cancer model.
- To assess the impact of combining hPSMA-CAR T-cell therapy with anti-programmed death receptor 1 (PD-1) monoclonal antibody (mAb) treatment.
- To explore CAR T-cell trafficking, persistence, and potential immune modulation mechanisms in solid tumors.
Main Methods:
- Utilized a Myc-CaP:PSMA(+) prostate cancer model in immune-competent and immune-deficient mice.
- Developed and employed second-generation anti-hPSMA human CAR T-cells with a luciferase reporter for bioluminescence imaging (BLI).
- Administered hPSMA-CAR T-cells alone and in combination with anti-hPD1 mAb, monitoring tumor growth and CAR T-cell activity via BLI.
Main Results:
- PD-L1 expression was detected in tumors, and endogenous T-cells were excluded from tumor centers in immune-competent mice.
- Anti-PD-1 treatment reversed T-cell exclusion and induced a tumor treatment response.
- Combination therapy of hPSMA-CAR T-cells and anti-PD-1 enhanced antitumor efficacy but resulted in short-lived responses.
- Observed an 'inverse pattern' of CAR T-cell BLI intensity, suggesting signal loss and/or reduced cell numbers post-activation.
- Decreased T-cell mitochondrial function following activation may limit bioluminescence signal intensity.
Conclusions:
- hPSMA-CAR T-cell immunotherapy combined with PD-1 blockade shows enhanced antitumor activity in prostate cancer models.
- Limited CAR T-cell persistence and function suggest the presence of other immune suppressive mechanisms in the tumor microenvironment.
- Further research into immune modulation strategies is necessary to improve the long-term efficacy of CAR T-cell therapy for solid tumors.
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