Authors: Li Zhang, Meenal Sinha, Sumit Kumar Subudhi, Brandon Chen, Jaqueline Marquez, Eric Liu, Kathryn Allaire, Alexander Cheung, Sharon Ng, Christopher Nguyen, Terence W. Friedlander, Rahul Raj Aggarwal, Matthew Spitzer, James Patrick Allison, Eric Jay Small, Padmanee Sharma, Lawrence Fong
Published: 2021-06-02
DOI: 10.1200/jco.2021.39.15_suppl.5045
Source: Full article
5045 Background: SipT is an FDA-approved autologous cellular immunotherapy targeting Prostatic Acid Phosphatase (PAP) that improves survival in patients with mCRPC. Combining immunotherapies could provide opportunities to enhance efficacy. We performed a randomized phase II trial adding CTLA-4 blockade with Ipi following SipT treatment and assessed whether timing of this sequence could modify immune and/or clinical responses to this treatment. Methods: Fifty chemotherapy-naïve mCRPC pts were randomized to receive ipi (4 doses of 3mg/kg every 3 weeks) either immediately (n = 24) or 3 weeks (n = 26) following completion of sipT. Blood was collected at various time points of the study. Immune-related adverse events (irAE) were recorded. The primary endpoint was to determine the proportion of pts who achieved an antibody titer of ³1:400 to PA2024, the targeting cassette in SipT and/or PAP. Clinical response was defined as ³30% reduction in serum prostate specific antigen (PSA) compared to pre-treatment levels. Radiographic progression-free survival (rPFS) and overall survival (OS) were defined as from the date of randomization to the date of radiographic progression and the date of death, respectively, or last follow-up date. Luminex assays for anti-PAP and anti-PA2024 specific serum IgG and ELISpot for IFN-g production against PAP and PA2024 were used to assess antigen-specific B and T cells responses, respectively. Modulation of circulating immune cells was evaluated by CyTOF. Results: SipT + Ipi did not induce any unexpected irAEs. The timing of Ipi did not significantly alter the rates of clinical response, rPFS, OS, toxicity, nor antigen-specific B and T cell responses. Clinical responses were observed in 6 of 50 (12%) pts and were often durable (median 140 days, range 55-689 days). Pts experiencing irAEs were more likely to have a PSA response (P = 0.001). The median rPFS was 5.7 months (mos). The median OS was 31.9 mos. This treatment induced antibody and T cell immune responses irrespective of treatment arm. Single cell assessment bt CyTOF demonstrated that treatment induced CD4 and CD8 T cell activation that was more pronounced with the immediate schedule. Lower frequencies of CTLA-4 positive circulating T cells were associated with better clinical outcomes even at baseline. Lower frequencies of CTLA-4 positive T cells was associated with prior radiation therapy. Prior radiation treatment was associated with improved rPFS (6.5 vs. 3.9 mos, P = 0.004). Conclusions: These findings suggest that pre-existing immunity may help dictate responsiveness to Ipi and SipT combination immunotherapy in mCRPC pts. Prior radiation therapy seems to leave not only a lasting impression on the T cell compartment, but also can associate with improved clinical outcomes with subsequent immunotherapy. Clinical trial information: NCT01804465.