Anti-prostate-specific membrane antigen (PSMA) monoclonal antibody (mAb) J591 immunotherapy for prostate cancer

Background

PSMA is a highly restricted cell-surface protein whose expression is increased with grade, stage, and attenuated AR signaling. J591 is a mAb against the external domain of PSMA and has demonstrated safety in numerous human-studies with anti-tumor activity when radiolabeled and conjugated with drug, with PSA and CTC declines. It was originally engineered to elicit antibody-dependent cellular cytotoxicity (ADCC) and we have made 2 important options leading to the current prospective clinical trials. First, studies of ¹⁷⁷Lu-J591 have demonstrated >90% CTC control. While initially thought to represent delivery of ¹⁷⁷Lu into CTCs and tumors, we retrospectively observed 4 of 7 patients with CTC count decline with a small amount (20 mg) of J591 without an effector molecule when used for imaging. Second, we analyzed long-term follow up from a 2001 study in men with biochemically recurrent or metastatic CRPC where men received unlabeled J591 plus low dose IL-2. Using validated nomograms, pen with biochemical relapse survived a median on 87 months longer than predicted without metastatic disease and in the pre-docetaxel era, men with mCRPC lived a median of 28.5 months longer than predicted. Based upon the preliminary data pointing towards CTC clearance and long-term survival, we have launched 2 prospective clinical trials.

Trial design

In study 1 [NCT02552394], men with progressive mCRPC by PCWG2 criteria and unfavorable CTC counts (>5 by CellSearch) on a stable hormonal regimen will receive a single dose of J591 in dose de-escalation cohorts followed by an expansion cohort at the lowest dose level with >4 of 6 men responding (i.e. achieve CTC 4 of the initial 10 men achieve the primary endpoint of peri-tumoral inflammation, an additional 20 will be treated. Additional endpoints include ADCC and lymphocyte subset analysis. Both studies include ⁸⁹Zr-J591 PET/CT (pre- and post-therapy for the mCRPC CTC study and pre-op for the prostatectomy study). Each study has received IRB and FDA clearance and have begun enrollment.

Clinical trial identification

Clinicaltrials.gov NCT02552394 and NCT02693860

Legal entity responsible for the study

N/A

Funding

Weill Cornell Medicine

Disclosure

N. Bander: Patent holder for J591.

All other authors have declared no conflicts of interest.