Abstract CT143: Results of combined targeting of prostate-specific membrane antigen (PSMA) with alpha-radiolabeled antibody 225Ac-J591 and beta-radiolabeled ligand 177Lu-PSMA I&T: preclinical and initial phase 1 clinical data in patients with metastatic castration-resistant prostate cancer (mCRPC)

Abstract

Background: PSMA is overexpressed by the majority of PC and may be targeted by both antibodies (mAb) and small molecule ligands (SML), each with differing PSMA binding sites, kinetics, and biodistributions. mAbs have long circulating times (exposing organs such a bone marrow) but are too large to target normal tissue luminal PSMA expression in salivary glands, small bowel, and kidney; SMLs rapidly diffuse to all PSMA+ sites and are excreted by the kidneys within hours. Alpha emitters have high potency over a short range whereas beta emitters have lower energy over a significantly longer range. We hypothesized that combining mAb and SML targeting plus combining alpha and beta emitters offered complementary benefits and would be safe and effective. Methods: A series of cell line and xenograft studies were performed to test mAb vs SML vs combo binding, uptake, and efficacy. A phase I/II clinical trial was initiated, enrolling patients with progressive, PSMA+ (by PSMA PET) mCRPC following potent AR pathway inhibition and chemotherapy (or chemo ineligible/refused)[NCT04886986]. The primary endpoint of phase I is assessment of dose-limiting toxicity (DLT) with secondary endpoints of response, progression-free and overall survival, genomic and imaging correlatives, and patient-reported outcomes. Results: Binding studies demonstrated that mAb plus SML binding was additive rather than competitive in LNCaP and CWR22Rv1 cell lines. Uptake of 177Lu-mAb plus -SML in LNCaP, CWR22rv1, and PC3/PSMA xenograft models demonstrated synergism, with 44-65% greater tumor radioactivity in combination than the sum of the individual agents. Intracellular tracking studies indicate that the mAb re-directs SML to lysosomes from recycling endosomes, maintains retention of SML in tumor cells, and, therefore, prolongs intra-tumoral radioactivity exposure. Survival was prolonged in animals receiving 225Ac-mAb plus 177Lu-SML vs either drug alone (or control). Nine men with median age 68 (range 55-87), PSA 140 (2.4-9614) have been enrolled in both of 2 planned dose-escalation cohorts. 89% with bone, 44% lymph node, 22% liver, 22% lung metastases; 88% with detectable CTC count (75% unfavorable). All had at least 1 metastatic lesion with PSMA PET SUVmax > liver SUVmean, with SUVmax of the single hottest lesion ranging from 11.6-69.9. For the primary endpoint, 0 of 3 with DLT in cohort 1, and with follow up ongoing, no DLT has occurred to date in 6 patients in cohort 2. Of evaluable patients, 5 of 6 with PSA decline (8-97% decline). Conclusions: Targeting PSMA with the combination of mAb and SML leads to synergistic radioactivity in preclinical studies. The combination on mAb and SML radiolabeled with alpha and beta emitters appears safe with short-term follow up with phase 2 enrollment planned. Citation Format: Scott T. Tagawa, Edward Fung, Muhammad O. Niaz, Mahelia Bissassar, Sharon Singh, Amie Patel, Angela Tan, Juana Martinez Zuloaga, Sandra Huicochea Castellanos, Jones T. Nauseef, Ana Molina, Cora Sternberg, David M. Nanus, Joseph Osborne, Neil H. Bander. Results of combined targeting of prostate-specific membrane antigen (PSMA) with alpha-radiolabeled antibody 225Ac-J591 and beta-radiolabeled ligand 177Lu-PSMA I&T: preclinical and initial phase 1 clinical data in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT143.

Prostate-Specific Membrane Antigen–Targeting Alpha Emitter via Antibody Delivery for Metastatic Castration-Resistant Prostate Cancer: A Phase I Dose-Escalation Study of 225Ac-J591

“…7,18,33 A post hoc observation (given in detail in Appendix 1) that two of three patients with liver metastases in this trial had a decrease in measurable tumor volume in the liver after 225 Ac-J591 with a fourth patient experiencing stable subcentimeter liver metastases is consistent with preclinical data that antibodies with longer circulation time have better uptake than small molecules in cells with lower PSMA expression. 34 While the longer half-life of Abs provides increased tumor exposure and improved uptake in tumors, particularly those with lower PSMA expression, the longer half-life likely plays a role in off-target toxicity in the form of bone marrow exposure and myelotoxicity. We hypothesize that although the energy level is much higher with alpha emitters, because of their shorter range, myelosuppression may be less significant.…”

Actinium-225 targeted alpha particle therapy for prostate cancer

“…This trial demonstrated safety in administering a single dose of [ 225 Ac]Ac-J591 to patients with pretreated progressive mCRPC. The safety profile, dosimetry, and therapeutic potential of the combination of the small molecule [ 177 Lu]Lu-PSMA I&T and the [ 225 Ac]Ac-J591 are also being studied to utilize the complimentary benefits of two therapies in mCRPC patients 72 .…”

“…In this context, the use of mAb ([ 225 Ac]Ac-J591) and [ 177 Lu]Lu-PSMA-I&T showed improved binding and higher radiation dose delivery compared to a single agent, resulting in a synergistic therapeutic efficiency in xenograft models. Clinical studies are in progress on mCRPC patients to find the maximum tolerated dose for the combination treatment of PSMA targeting [ 225 Ac]Ac-J591 and [ 177 Lu]Lu-PSMA-I&T (NCT04886986) 70 , 72 . As TAT is known to produce DNA damage as well as activation of immunogenic response, the use of [ 225 Ac]Ac-J591 in combination with pembrolizumab (PD-1 inhibitor) is being tested in PCa patients (NCT04946370) 76 .…”

Prostate specific membrane antigen binding radiopharmaceuticals: Current data and new concepts

“…Preclinical data indicate that monoclonal (J591) PSMA binding may result in more sustained uptake of radiolabeled PSMA small molecules ( 177 Lu-PSMA-617), and more cell kill ( 55 ). If true in the clinic, this would provide a strong rationale for combining a monoclonal with a radiolabeled therapeutic PSMA small molecule.…”