Immunotherapy resistance driven by loss of NY-ESO-1 expression in response to transgenic adoptive cellular therapy with PD-1 blockade.

BACKGROUND

The tumor antigen NY-ESO-1 has been shown to be an effective target for transgenic adoptive cell therapy (ACT) for the treatment of sarcoma and melanoma. However, despite frequent early clinical responses, many patients ultimately develop progressive disease. Understanding the mechanisms underlying treatment resistance is crucial to improve future ACT protocols. Here, we describe a novel mechanism of treatment resistance in sarcoma involving loss of expression of NY-ESO-1 in response to transgenic ACT with dendritic cell (DC) vaccination and programmed cell death protein-1 (PD-1) blockade.

METHODS

A HLA-A*02:01-positive patient with an NY-ESO-1-positive undifferentiated pleomorphic sarcoma was treated with autologous NY-ESO-1-specific T-cell receptor (TCR) transgenic lymphocytes, NY-ESO-1 peptide-pulsed DC vaccination, and nivolumab-mediated PD-1 blockade.

RESULTS

Peripheral blood reconstitution with NY-ESO-1-specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. There was initial tumor regression, and immunophenotyping of the peripheral transgenic T cells showed a predominantly effector memory phenotype over time. Tracking of transgenic T cells to the tumor sites was demonstrated in on-treatment biopsy via both TCR sequencing-based and RNA sequencing-based immune reconstitution, and nivolumab binding to PD-1 on transgenic T cells was confirmed at the tumor site. At the time of disease progression, the promoter region of NY-ESO-1 was found to be extensively methylated, and tumor NY-ESO-1 expression was completely lost as measured by RNA sequencing and immunohistochemistry.

CONCLUSIONS

ACT of NY-ESO-1 transgenic T cells given with DC vaccination and anti-PD-1 therapy resulted in transient antitumor activity. NY-ESO-1 expression was lost in the post-treatment sample in the setting of extensive methylation of the NY-ESO-1 promoter region.

BIOLOGICAL/CLINICAL INSIGHT

Antigen loss represents a novel mechanism of immune escape in sarcoma and a new point of improvement in cellular therapy approaches.

TRIAL REGISTRATION NUMBER

NCT02775292.

Informations de copyright

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: TSN received honoraria from consulting with Allogene Therapeutics, PACT Pharma, and Adaptive Biotechnologies. AR received honoraria from consulting with Amgen, Bristol-Myers Squibb, Chugai, Genentech, Merck, and Novartis; is or has been a member of the scientific advisory board; and holds stock in Advaxis, Arcus Biosciences, Compugen, CytomX, Five Prime, RAPT, Highlight, ImaginAb, Isoplexis, Kite-Gilead, Lutris Pharma, Merus, Rgenix, and Tango Therapeutics. AS received honoraria from consulting with Daiichi Sankyo, Aadi Biosciences, and Deciphera; is on the board of directors; holds stock in Certis Oncology Solutions; and has provided institutional support for clinical trials for RAIN Therapeutics, Ayala Therapeutics, and Tracon.