582 Immune correlates from QuEST1 in men with castration-resistant prostate cancer

BackgroundImmune checkpoint inhibitors have limited efficacy in unselected metastatic castration-resistant prostate cancer (mCRPC) patients. Combination immunotherapy approaches to generate a tumor-directed immune response (vaccine) and facilitate the resulting anti-tumor immune activity (checkpoint inhibitors, cytokines) have shown synergy preclinically. In the phase I/II Quick Efficacy Seeking Trial (QuEST1, NCT03493945), combination of a brachyury-targeting vaccine (BN-brachyury), TGF-β/anti-PD-L1 blocking bifunctional fusion protein (bintrafusp alfa), and IL-15 superagonist (N-803) have produced preliminary evidence of efficacy in CRPC, with 5/12 patients having a sustained prostate-specific antigen (PSA) response that included 2 radiographic partial responses, compared to 1/13 patients who received BN-brachyury plus bintrafusp alfa. Here, we present immune correlates from patients enrolled in Arm 2.1A (BN-brachyury + bintrafusp alfa) and Arm 2.2A (BN-brachyury + bintrafusp alfa + N-803).MethodsPeripheral blood mononuclear cells (PBMC) and serum were obtained from 25 patients pre and multiple time points post treatment. PBMCs were assessed for antigen specific T cells targeting brachyury and MUC-1 by intracellular cytokine staining, 158 peripheral immune cell subsets by multicolor flow cytometry, and TCRVβ sequencing. Patients were also evaluated for complete blood counts, and serum cytokines/soluble factors using ELISA assays and OLINK’s immuno-oncology panel. Immune parameters were compared between Arm 2.1A and Arm 2.2A and evaluated for associations with clinical response in Arm 2.2A.ResultsBrachyury and MUC-1 specific T cells were increased in most patients post treatment in both arms. A greater increase in total NK cells, refined NK subsets expressing markers of activation/adhesion, and TCR diversity was observed after 2 weeks of therapy in Arm 2.2A than Arm 2.1A. Absolute lymphocyte counts and serum levels of granzyme B, sCD27, and sCD40L were also increased after 2 weeks in Arm 2.2A compared to Arm 2.1A. Serum proteomic analyses revealed a greater increase in analytes related to NK cell signaling in Arm 2.2A than Arm 2.1A. Specific immune parameters at baseline associated with development of clinical response in patients treated in Arm 2.2A; responders had trends of higher frequencies of CD4+ and CD8+ T cells, lower frequencies of MDSCs and monocytes, and lower levels of serum IL-6 and sCD40 than non-responders.ConclusionsThese findings demonstrate enhanced immune activation of both NK and T cells with the addition of N-803 in Arm 2.2A, where more clinical activity was observed than in Arm 2.1A. These findings support the continued evaluation of the combination of BN-brachyury, bintrafusp alfa, and N-803 in patients with mCRPC.AcknowledgementsThis research was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health, and via Cooperative Research and Development Agreements (CRADAs) between the NCI and EMD Serono, the NCI and Bavarian Nordic, and the NCI and ImmunityBio.Trial RegistrationNCT03493945Ethics ApprovalThe trial was approved by the Institutional Review Board of the Center for Cancer Research, National Cancer Institute (ClinicalTrials.gov identifier: NCT03493945).

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

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002254 ◽

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.

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Abstract 5512: Immune correlates of clinical response and survival in castration-resistant prostate cancer patients treated with prostate GVAX and anti-CTLA4 immunotherapy

10.1158/1538-7445.am2011-5512 ◽

2011 ◽

Cited By ~ 1

Author(s):

Saskia J.A.M. Santegoets ◽

Alfons J.M. van den Eertwegh ◽

Anita G.M. Stam ◽

Rik J. Scheper ◽

Sinéad M. Lougheed ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Response ◽

Cancer Patients ◽

Castration Resistant Prostate Cancer ◽

Immune Correlates ◽

Castration Resistant ◽

Prostate Gvax

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Putting the Pieces Together: Completing the Mechanism of Action Jigsaw for Sipuleucel-T

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djaa021 ◽

2020 ◽

Vol 112 (6) ◽

pp. 562-573

Author(s):

Ravi A Madan ◽

Emmanuel S Antonarakis ◽

Charles G Drake ◽

Lawrence Fong ◽

Evan Y Yu ◽

...

Keyword(s):

Prostate Cancer ◽

Immune Response ◽

T Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Phase Iii ◽

Immune Memory ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant

Abstract Sipuleucel-T is an autologous cellular immunotherapy that induces an immune response targeted against prostatic acid phosphatase (PAP) to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. In the phase III IMPACT study, sipuleucel-T was associated with a statistically significantly increased overall survival (OS) (median = 4.1 months) vs placebo. Patients with baseline prostate-specific antigen levels in the lowest quartile (≤22.1 ng/mL) exhibited a 13-month improvement in OS with sipuleucel-T. Together, this led sipuleucel-T to be approved and recommended as first-line therapy in various guidelines for treatment of metastatic castration-resistant prostate cancer. This review discusses the varied findings about the mechanisms of action of sipuleucel-T, bringing them together to form a more coherent picture. These pieces include inducing a statistically significant increase in antigen-presenting cell activation; inducing a peripheral immune response specific to the target (PAP) and/or immunizing (PA2024) antigens; stimulating systemic cytotoxic T-lymphocyte activity; and mediating antigen spread (ie, increased antibody responses to secondary proteins in addition to PAP and PA2024). Each of these pieces individually correlates with OS. Sipuleucel-T also traffics T cells to the prostate and is associated with long-term immune memory such that a second course of treatment induces an anamnestic immune response. Prostate cancer does not have a strongly inflamed microenvironment, thus its response to immune checkpoint inhibitors is limited. Because sipuleucel-T is able to traffic T cells to the tumor, it may be an ideal combination partner with immunotherapies including immune checkpoint inhibitors or with radiation therapy.

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

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.125 ◽

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.

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