
==== Front
medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.09.09.24313308
preprint
1
Article
Neoadjuvant androgen deprivation therapy with or without Fc-enhanced non-fucosylated anti-CTLA-4 (BMS-986218) in high risk localized prostate cancer: a randomized phase 1 trial
Ager Casey R. http://orcid.org/0000-0003-0507-700X

Obradovic Aleksandar http://orcid.org/0000-0002-8009-0186

McCann Patrick http://orcid.org/0000-0002-1836-4617

Chaimowitz Matthew
Wang Alexander L. E.
Shaikh Neha
Shah Parin http://orcid.org/0000-0003-4648-7830

Pan Samuel
Laplaca Caroline J.
Virk Renu K.
Hill Jessica C.
Jugler Collin http://orcid.org/0000-0001-9207-7539

DeFranco Grace http://orcid.org/0000-0002-6037-9425

Bhattacharya Nilika
Scher Howard I.
DeCastro Guarionex Joel http://orcid.org/0000-0002-1166-3454

Anderson Christopher B.
McKiernan James M.
Spina Catherine S. http://orcid.org/0000-0001-6067-5024

Stein Mark N. http://orcid.org/0000-0002-0853-3640

Runcie Karie http://orcid.org/0000-0002-0598-7663

Drake Charles G.
Califano Andrea http://orcid.org/0000-0003-4742-3679

Dallos Matthew C. http://orcid.org/0000-0002-5412-3490

11 9 2024
2024.09.09.24313308https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://medrxiv.org/lookup/doi/10.1101/2024.09.09.24313308
nihpp-2024.09.09.24313308.pdf
Abstract

Men with high-risk localized prostate cancer exhibit high rates of post-surgical recurrence. In these patients, androgen deprivation therapy (ADT) is immunomodulatory, however increased infiltration of regulatory T cells (Tregs) may limit the antitumor immune effects of ADT. We designed a neoadjuvant clinical trial to test whether BMS-986218 – a next-generation non-fucosylated anti-CTLA-4 antibody engineered for enhanced antibody-dependent cellular cytotoxicity or phagocytosis (ADCC/P) – depletes intratumoral Tregs and augments the response to ADT. In this single-center, two-arm, open-label study, 24 men with high-risk localized prostate cancer were randomized to receive a single dose of ADT with or without two pre-operative doses of BMS-986218 (anti-CTLA4-NF) prior to radical prostatectomy. Treatment was well tolerated and feasible in the neoadjuvant setting. A secondary clinical outcome was the rate of disease recurrence, which was lower than predicted in both arms. Mechanistically, anti-CTLA4-NF reduced ADT-induced Treg accumulation through engagement of CD16a/ FCGR3A on tumor macrophages, and depth of Treg depletion was quantitatively associated with clinical outcome. Increased intratumoral dendritic cell (DC) frequencies also associated with lack of recurrence, and pre-clinical data suggest ADCC/P-competent anti-CTLA-4 antibodies elicit activation and expansion of tumor DCs. Patients receiving anti-CTLA4-NF also exhibited phenotypic signatures of enhanced antitumor T cell priming. In total, this study provides the first-in-human evidence of Treg depletion by glycoengineered antibodies targeting CTLA-4 in humans and their potential in combination with ADT in prostate cancer patients with high-risk of recurrence.
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