3304 - A Pilot Study of Immunological Response to PSMA-Directed Radioligand Therapy for the Treatment of Oligometastatic Prostate Cancer

L. Valle¹, L. B. James-Allan², A. Franco³, C. Felix¹, E. Rietdorf⁴, J. Czernin⁵, M. L. Steinberg¹, N. G. Nickols⁶, M. Rettig⁷, J. B. Weidhaas¹, J. Calais⁸, and A. U. Kishan¹; ¹Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, ²UCLA, Los Angeles, CA, ³California University of Science and Medicine, Colton, CA, ⁴UCLA Department of Radiation Oncology, Los Angeles, CA, ⁵Ahmanson Translational Theranostics Division, University of California, Los Angeles, Los Angeles, CA, ⁶University of California Los Angeles, Department of Radiation Oncology, Los Angeles, CA, ⁷Department of Medical Oncology, University of California, Los Angeles, Los Angeles, CA, ⁸., Los Angeles, CA

Purpose/Objective(s): Clinical evidence supporting prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is increasing in metastatic prostate cancer (PC), though a comprehensive understanding of the mechanistic underpinnings of systemic tumor control remains to be elucidated. We sought to evaluate the impact of RLT on immune stimulation in patients with oligometastatic PC and hypothesized that RLT would result in immune stimulation as evaluated by the indices of productive rearrangements (ie unique rearrangements that produce a functional T-cell receptor) and Simpson’s clonality (the square root of Simpson’s diversity index for productive rearrangements). Materials/

Methods: The LUNAR trial is a randomized phase II study evaluating the benefit of augmenting oligometastasis-directed SBRT with PSMA-targeted RLT in men with oligorecurrent hormone sensitive PC. Patients are randomized 1:1 to receive either MDT with SBRT to all sites of disease (control arm) or two cycles of neoadjuvant 177Lu-PNT2002 (6.8 GBq) followed by SBRT to all sites of disease (experimental arm). 10 patients from the LUNAR trial were included in this pilot study. 5 patients who experienced rapid progression on the control arm were matched by stage, number of lesions, and pre-treatment PSA to 5 patients from the experimental arm with disease control. Translational blood was collected at pre-treatment baseline and at 3-month follow-up from completion of all therapy. PBMCs were isolated and the CDR3 of the T-cell receptor beta (TCRB) was sequenced using a multiplex PCR-based approach (Adaptive Biosciences, Seattle, WA). One way ANOVA compared mean Simpson’s clonality and mean productive rearrangements between baseline and 3-month follow-up timepoints in the 5 control patients and a parallel comparison was made in the 5 experimental patients.
Results: Median number of treated oligometastatic lesions from patients on the control and experimental arms were 1 and 2, respectively. Mean change in PSA from baseline to 3-month follow-up was +40.2 ng/ml in the control patients and -1.7 ng/ml in the experimental patients. Mean productive rearrangements decreased from 322,619 to 254,813 (p=0.69) in the control patients and decreased from 409,785 to 302,131 (p=0.41) in the experimental patients. Mean Simpson’s clonality increased from 0.05 to 0.06 (p=0.87) in the control patients and remained unchanged at 0.04 (p=0.99) in the experimental patients.
Conclusion: In this small pilot study representing the first evaluation of the impact of PSMA-directed RLT on TCRB receptors in oligometastatic prostate cancer, RLT did not appear to result in significant stimulation of the T-cell repertoire of the peripheral immune system beyond SBRT alone, nor was antigen-specific clonal selection evident at early follow-up, though statistical power was likely insufficient. Additional testing to better elucidate potential immunologic effects of RLT on tumor control at additional timepoints is warranted.