Breast Cancers Are Immunogenic: Immunologic Analyses and a Phase II Pilot Clinical Trial Using Mutation-Reactive Autologous Lymphocytes.

Autor:	Zacharakis N; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Huq LM; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Seitter SJ; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Kim SP; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Gartner JJ; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Sindiri S; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Hill VK; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Li YF; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Paria BC; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Ray S; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Gasmi B; Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD., Lee CC; Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD., Prickett TD; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Parkhurst MR; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Robbins PF; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Langhan MM; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Shelton TE; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Parikh AY; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Levi ST; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Hernandez JM; Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD., Hoang CD; Thoracic Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Sherry RM; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.; Lyell Immunopharma, South San Francisco, CA., Yang JC; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Feldman SA; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford School of Medicine, Stanford, CA., Goff SL; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Rosenberg SA; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Jazyk:	angličtina
Zdroj:	Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2022 Jun 01; Vol. 40 (16), pp. 1741-1754. Date of Electronic Publication: 2022 Feb 01.
DOI:	10.1200/JCO.21.02170
Abstrakt:	Purpose: Metastatic breast cancer (mBrCa) is most often an incurable disease with only modest responses to available immunotherapies. This study investigates the immunogenicity of somatic mutations in breast cancer and explores the therapeutic efficacy in a pilot trial of mutation-reactive tumor-infiltrating lymphocytes (TILs) in patients with metastatic disease. Patients and Methods: Forty-two patients with mBrCa refractory to previous lines of treatment underwent surgical resection of a metastatic lesion(s), isolation of TIL cultures, identification of exomic nonsynonymous tumor mutations, and immunologic screening for neoantigen reactivity. Clinically eligible patients with appropriate reactivity were enrolled into one cohort of an ongoing phase II pilot trial of adoptive cell transfer of selected neoantigen-reactive TIL, with a short course of pembrolizumab (ClinicalTrials.gov identifier: NCT01174121). Results: TILs were isolated and grown in culture from the resected lesions of all 42 patients with mBrCa, and a median number of 112 (range: 6-563) nonsynonymous mutations per patient were identified. Twenty-eight of 42 (67%) patients contained TIL that recognized at least one immunogenic somatic mutation (median: 3 neoantigens per patient, range: 1-11), and 13 patients demonstrated robust reactivity appropriate for adoptive transfer. Eight patients remained clinically eligible for treatment, and six patients were enrolled on a protocol of adoptive cell transfer of enriched neoantigen-specific TIL, in combination with pembrolizumab (≤ 4 doses). Objective tumor regression was noted in three patients, including one complete response (now ongoing over 5.5 years) and two partial responses (6 and 10 months). Conclusion: Most patients with breast cancer generated a natural immune response targeting the expressed products of their cancer mutations. Adoptive transfer of TIL is a highly personalized experimental option for patients with mBrCa shown to be capable of mediating objective responses in this pilot trial and deserves further study. Competing Interests: Nikolaos ZacharakisPatents, Royalties, Other Intellectual Property: Provisional patents about TCRs filed and held by NIH (Inst) Sanghyun P. KimPatents, Royalties, Other Intellectual Property: I have filed a provisional patent that has no relationship to the current publication (Inst) Maria R. ParkhurstPatents, Royalties, Other Intellectual Property: Patent royalties Paul F. RobbinsPatents, Royalties, Other Intellectual Property: BioNTech US Inc—Royalty, Kite Pharma Inc—Royalty, Intellia Therapeutics Inc—Royalty, Intima Bioscience Inc—Royalty, Myst Therapeutics Inc—Royalty, Tailored Therapeutics Inc—Royalty, Ziopharm Oncology Inc—Royalty Richard M. SherryEmployment: Lyell Immunopharma James C. YangResearch Funding: Kite/Gilead (Inst)Patents, Royalties, Other Intellectual Property: Royalties on inventions may go to my institution (NCI), which may pass a portion (anonymously) to me Steven A. FeldmanConsulting or Advisory Role: Guidepoint Global, Kite, a Gilead Company, TCG Crossover Management LLCResearch Funding: Syncopation (Inst)Patents, Royalties, Other Intellectual Property: I have patents and resulting royalties from licensed patents from NCI/Surgery Branch, related to cellular immunotherapy Steven A. RosenbergResearch Funding: Kite, a Gilead Company (Inst), Iovance Biotherapeutics (Inst), ZIOPHARM Oncology (Inst)Patents, Royalties, Other Intellectual Property: Patents held by NIHNo other potential conflicts of interest were reported.
Databáze:	MEDLINE
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