177Lu-PSMA-617 (Pluvicto) Combo With Sipulecel-T in Phase 1 Trial

City of Hope Medical Center, in collaboration with the National Cancer Institute, is initiating a randomized phase 1 study in metastatic castration‑resistant prostate cancer (mCRPC) that compares lutetium Lu 177 vipivotide tetraxetan (177Lu‑PSMA‑617 or Pluvicto) alone versus the same radioligand combined with sipuleucel‑T, with the primary goal of quantifying the induced anti‑tumor immune response alongside safety and early efficacy signals. The prespecified primary endpoint is the anti‑prostatic acid phosphatase (PAP) immunoglobulin G response rate, defined by IgG titers greater than 400 between weeks 7 and 19, with secondary measures including anti‑PA2024 antibody titers, adverse events, PSA50 response, objective response, radiographic progression‑free survival, and overall survival.​

Patients are randomized to two arms: both receive 177Lu‑PSMA‑617 intravenously every 6 weeks for up to six cycles; the experimental arm adds sipuleucel‑T beginning in week 8, then every two weeks for up to three one‑hour infusions, integrating leukapheresis for product manufacturing and serial biospecimen collections. Imaging spans PSMA PET/CT, bone scans, and MRI, with post‑treatment follow‑up at 30 days, then every three months in year one and every six months thereafter until progression and survival follow‑up, ensuring standardized disease assessment across arms.​

The scientific rationale hinges on the capacity of targeted radionuclide therapy to provoke immunogenic cell death and remodel the tumor microenvironment, releasing danger‑associated molecular patterns (ATP, HMGB1, calreticulin, Annexin A1) and activating cGAS–STING signaling, thereby enhancing dendritic‑cell priming and T‑cell infiltration while also upregulating checkpoint ligands that shape combination strategies. Against this backdrop, sipuleucel‑T, an autologous cellular immunotherapy manufactured by leukapheresis and ex vivo activation with the recombinant PAP–GM‑CSF fusion protein PA2024, drives APC activation, PAP‑ and PA2024‑specific cellular and humoral responses, and clinically relevant antigen spread that correlate with overall survival, making it a mechanistically complementary partner to radioligand‑induced antigen release.​

The trial’s timing choice, adding sipuleucel‑T after initial cycles of 177Lu‑PSMA‑617, aligns with preclinical and translational insights suggesting sequential priming by radiopharmaceuticals followed by immune augmentation can leverage tumor‑antigen release and microenvironmental shifts while avoiding excessive radiation exposure to newly infused immune effectors. Consistent with this immunologic focus, the protocol’s immune readouts explicitly track anti‑PAP and anti‑PA2024 antibody titers as primary and secondary endpoints to quantify vaccine‑specific and immunizing‑antigen responses induced by the combination.​

Clinical context supports feasibility and relevance: in taxane‑naive mCRPC, the phase III PSMAfore study established that 177Lu‑PSMA‑617 (7.4 GBq every six weeks for six cycles) significantly prolonged radiographic PFS versus switching androgen receptor pathway inhibitors and maintained a favorable, well‑characterized safety profile, despite OS interpretation being confounded by high crossover to radioligand therapy.

Clinical trial.