A phase I clinical trial of PSMA-directed/TGFβ-insensitive CAR-T cells in metastatic castration-resistant prostate cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 125-125
Author(s):  
Vivek Narayan ◽  
Julie Barber-Rotenberg ◽  
Joseph Fraietta ◽  
Wei-Ting Hwang ◽  
Simon F. Lacey ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
Cell Expansion ◽  
Castration Resistant Prostate Cancer ◽  
Car T Cells ◽  
Castration Resistant ◽  
Car T ◽  
Tumor Biopsies ◽  
Dose Dependent

125 Background: Prostate specific membrane antigen (PSMA) is a highly expressed tumor-associated antigen potentially amenable to chimeric antigen receptor-modified T (CAR-T) cell therapy for castration-resistant prostate cancer (CRPC). However, a primary challenge to the success of CAR-T therapy in CRPC is the immunosuppressive microenvironment, characterized by high levels of TGFβ. The immunosuppressive functions of TGFβ can be inhibited in T cells using a dominant negative TGFβ receptor (TGFβRdn), thereby enhancing antitumor immunity. Methods: We conducted a first-in-human phase 1 clinical trial to evaluate the feasibility, safety and preliminary efficacy of PSMA-directed/TGFβ-insensitive CAR-T cells (CART-PSMA-TGFβRdn) in patients with metastatic CRPC (NCT03089203). In a 3+3 dose-escalation design, patients received a single dose of 1-3 x 107/m2 (Cohort 1) or 1-3 x 108/m2 (Cohort 2) CART-PSMA-TGFβRdn cells without lymphodepleting (LD) chemotherapy. In Cohort 3, one patient received 1-3 x 108/m2 CART-PSMA-TGFβRdn cells following a LD chemotherapy regimen of cyclophosphamide and fludarabine (Cy/Flu). In Cohort -3, three patients received 1-3 x 107/m2 CART-PSMA-TGFβRdn cells following Cy/Flu. Patients underwent metastatic tumor biopsies at baseline and on day 10 following treatment. Quantitative PCR of CART-PSMA-TGFβRdn DNA was performed at serial timepoints to evaluate for CAR-T expansion and persistence in peripheral blood and trafficking to target tissues. Multiplex cytokine analysis assessed CART-PSMA-TGFβRdn bioactivity. Results: Ten patients received CART-PSMA-TGFβRdn therapy across dose-level cohorts. All CART-PSMA-TGFβRdn infusion products met target transduction efficiency. Evaluation of CAR-T cellular kinetics demonstrated dose-dependent peripheral blood T cell expansion, as well as tumor tissue trafficking in post-treatment tumor biopsies. At Cohort 2 and above, 5 of 7 treated patients developed grade ≥2 cytokine release syndrome (CRS). Marked increases in inflammatory cytokines (IL-6, IL-15, IL-2, IFNγ) correlated with high-grade CRS events. One grade 5 adverse event (sepsis) occurred in Cohort 3. PSA decline was observed in 6 of 10 patients (median decline -33.2%, range -11.6% to -98.3%), and PSA30 response occurred in 4 of 10 patients (including one patient achieving PSA < 0.1 ng/mL). Conclusions: Adoptive cellular therapy with CART-PSMA-TGFβRdn is safe and feasible in patients with metastatic CRPC. A dose-dependent and lymphodepletion chemotherapy-dependent relationship was observed with CART-PSMA-TGFβRdn cell expansion, cytokine expression, CRS, and anti-tumor effect. Correlative cell trafficking and paired tumor Nanostring analyses will be presented. Future clinical investigations seek to enhance anti-tumor efficacy, while optimizing the therapeutic window. Clinical trial information: NCT03089203.

A phase I clinical trial of PSMA-directed/TGFβ-insensitive CAR-T cells in metastatic castration-resistant prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS269-TPS269
Author(s):  
Vivek Narayan ◽  
Whitney Gladney ◽  
Gabriela Plesa ◽  
Neha Vapiwala ◽  
Erica L. Carpenter ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
Single Dose ◽  
Peripheral Blood ◽  
Therapeutic Potential ◽  
Dominant Negative ◽  
Therapeutic Window ◽  
Car T Cells ◽  
Car T

TPS269 Background: Adoptive immunotherapy with Chimeric Antigen Receptor (CAR)-T cells is a novel approach for the treatment of prostate cancer. However, the prostate cancer immunosuppressive microenvironment, including high levels of TGFβ, may limit the therapeutic potential of re-directed T cells upon tumor infiltration. The inhibition of TGFβ signaling via co-expression of a dominant negative TGFβ receptor (TGFβRdn) can enhance antitumor immunity. Co-expression of TGFβRdn on PSMA-redirected CAR-T cells in in vivo disseminated tumor models led to increased T cell proliferation, enhanced cytokine secretion, resistance to exhaustion, long-term persistence, and greater induction of tumor eradication. Methods: We are conducting a first-in-human phase 1 clinical trial evaluating the safety and preliminary efficacy of lentivirally-transduced PSMA-redirected/TGFβ-insensitive CAR-T cells (CART-PSMA-TGFβRdn) in metastatic CRPC (NCT03089203). In a 3+3 dose-escalation design, patients received a single dose of 1-3 x 107/m2 (Cohort 1) or 1-3 x 108/m2 (Cohort 2) CART-PSMA-TGFβRdn cells without lymphodepleting chemotherapy. In Cohort 3, 1-3 x 108/m2 CART-PSMA-TGFβRdn cells are administered following a lymphodepleting chemotherapy regimen of cyclophosphamide and fludarabine (cy/flu). A currently accruing modified protocol seeks to optimize the therapeutic window with CART-PSMA-TGFβRdn (CAR-T dose of 1-3 x 107/m2 following lymphodepleting cy/flu). Eight patients have received a single dose of CART-PSMA-TGFβRdn. CAR-T expansion and persistence in peripheral blood and trafficking to target tissues is evaluated via quantitative PCR of CART-PSMA-TGFβRdn DNA. Bioactivity of CAR-T cells in peripheral blood is evaluated via multiplex immunoassays. Additional correlative analyses will interrogate the therapeutic contribution of TGFβRdn, as well as early markers of response and resistance to CART-PSMA-TGFβRdn therapy. Clinical trial information: NCT03089203.

scholarly journals Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer

2021 ◽  
Vol 9 (5) ◽  
pp. e002254
Author(s):  
Meenal Sinha ◽  
Li Zhang ◽  
Sumit Subudhi ◽  
Brandon Chen ◽  
Jaqueline Marquez ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Clinical Response ◽  
T Cell Responses ◽  
Castration Resistant Prostate Cancer ◽  
Cell Responses ◽  
Castration Resistant ◽  
Clinical Responses

BackgroundSipuleucel-T is a US Food and Drug Administration-approved autologous cellular immunotherapy that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We examined whether administering ipilimumab after sipuleucel-T could modify immune and/or clinical responses to this treatment.MethodsA total of 50 patients with mCRPC were enrolled into a clinical trial (NCT01804465, ClinicalTrials.gov) where they received ipilimumab either immediately or delayed 3 weeks following completion of sipuleucel-T treatment. Blood was collected at various timepoints of the study. Luminex assay for anti-prostatic acid phosphatase (PAP) and anti-PA2024-specific serum immunoglobulin G (IgG) and ELISpot for interferon-γ (IFN-γ) production against PAP and PA2024 were used to assess antigen-specific B and T cell responses, respectively. Clinical response was defined as >30% reduction in serum prostate-specific antigen levels compared with pretreatment levels. The frequency and state of circulating immune cells were determined by mass cytometry by time-of-flight and statistical scaffold analysis.ResultsWe found the combination to be well tolerated with no unexpected adverse events occurring. The timing of ipilimumab did not significantly alter the rates of antigen-specific B and T cell responses, the primary endpoint of the clinical trial. Clinical responses were observed in 6 of 50 patients, with 3 having responses lasting longer than 3 months. The timing of ipilimumab did not significantly associate with clinical response or toxicity. The combination treatment did induce CD4 and CD8 T cell activation that was most pronounced with the immediate schedule. Lower frequencies of CTLA-4 positive circulating T cells, even prior to treatment, were associated with better clinical outcomes. Interestingly, these differences in CTLA-4 expression were associated with prior localized radiation therapy (RT) to the prostate or prostatic fossa. Prior radiation treatment was also associated with improved radiographic progression-free survival.ConclusionCombining CTLA-4 blockade with sipuleucel-T resulted in modest clinical activity. The timing of CTLA-4 blockade following sipuleucel-T did not alter antigen-specific responses. Clinical responses were associated with both lower baseline frequencies of CTLA-4 expressing T cells and a history of RT. Prior cancer therapy may therefore result in long-lasting immune changes that influence responsiveness to immunotherapy with sipuleucel-T and anti-CTLA-4.

A phase I clinical trial of PSMA-directed/TGFβ-insensitive CAR-T cells in metastatic castration-resistant prostate cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS347-TPS347 ◽  
Author(s):  
Vivek Narayan ◽  
Whitney Gladney ◽  
Gabriela Plesa ◽  
Neha Vapiwala ◽  
Erica Carpenter ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Phase 1 ◽  
Dominant Negative ◽  
Car T Cells ◽  
Car T

TPS347 Background: Adoptive immunotherapy with Chimeric Antigen Receptor (CAR)-T cells has transformative potential for the treatment of cancer. However, a primary challenge to the success of these therapies in prostate cancer is the immunosuppressive microenvironment, including high levels of Transforming Growth Factor-beta (TGFβ), encountered by re-directed T cells upon tumor infiltration. Importantly, these immunosuppressive functions of TGFβ can be abrogated in T cells using a dominant negative TGFβ receptor (TGFβRdn), thereby enhancing antitumor immunity. In in vivo disseminated prostate cancer models, co-expression of TGFβRdn on PSMA-redirected CAR-T cells led to increased T cell proliferation, enhanced cytokine secretion, resistance to exhaustion, long-term persistence, and greater tumor eradication. Methods: We initiated a first-in-human phase 1 clinical trial to evaluate the safety and preliminary efficacy of lentivirally-transduced PSMA-directed/TGFβ-insensitive CAR-T cells (CART-PSMA-TGFβRdn) in men with metastatic CRPC. In preliminary dose-escalation cohorts, patients received a single dose of 1-3 x 107/m2 (Cohort 1) or 1-3 x 108/m2 (Cohort 2) CART-PSMA-TGFβRdn cells without lymphodepleting chemotherapy in a 3+3 design. In Cohort 3, patients will receive the MTD of CART-PSMA-TGFβRdn following a lymphodepleting regimen of cyclophosphamide and fludarabine. All patients provide newly obtained metastatic tumor biopsies at baseline, as well as on day +10 following the CAR-T cell infusion and at disease progression. CAR-T expansion and persistence in peripheral blood and trafficking to target tissues is evaluated via quantitative PCR of CART-PSMA-TGFβRdn DNA. Bioactivity of CART-PSMA-TGFβRdn cells is evaluated via multiplex immunoassays. Additional correlative studies include enumeration and phenotyping of circulating tumor cells and DNA. Cohorts 1 and 2 have been completed without observed DLT. Interestingly, a reversible cytokine release syndrome has been observed that is responsive to tocilizumab. Enrollment in Cohort 3 began in September 2018. Cohort expansions will examine serial CART-PSMA-TGFβRdn re-treatment strategies. Clinical trial information: NCT03089203.

Sign in / Sign up

Export Citation Format

Share Document