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

Abstract

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.

Progress and Prospect of Immunotherapy for Triple-Negative Breast Cancer

“…Zacharakis and colleagues reported that one patient with metastatic breast cancer who was treated with TILs reactive against the mutant versions of four proteins (SLC3A2, KIAA0368, CADPS2, and CTSB) in conjunction with IL-2 and the checkpoint blockade mediated the complete durable regression of metastatic breast cancer for >22 months, revealing a novel immunotherapy approach for the treatment of breast cancers ( 83 ). After the initial case report of treatment using TIL, Zacharakis and colleagues reported a preliminary result of a pilot trial of mutation-reactive TILs in patients with metastatic breast cancer ( 84 ). They were able to isolate and grow TILs in culture from the resected lesions of all 42 patients.…”

Implications for Immunotherapy of Breast Cancer by Understanding the Microenvironment of a Solid Tumor

“…Nevertheless, all the combination approaches broadly weaken the TME either through the influence of cell dividing processes through chemotherapy or immunomodulation using CPIs. This is done either before or at the same time as the cellular therapy is administered [88][89][90][91][92][93][94][95][96]. However, chemotherapy and CPIs are administered systematically, which widens the side effect profile.…”

Neoantigens and NK Cells: “Trick or Treat” the Cancers?

“…Another clinical trial in a metastatic breast cancer patient found that adoptive transfer of TILs reactive against neoepitopes derived from four proteins combined with interleukin-2 and ICB resulted in complete durable regression for over 22 months ( 53 ), implying clinical benefits of combining ACT with other immunomodulators such as the checkpoint inhibitor. At the same, after adoptive transfer of enriched neoantigen-specific TILs combined with anti-PD-1 antibody pembrolizumab in a phase II pilot trial, three of the six patients with metastatic breast cancer showed objective tumor regression, including one complete response that was ongoing for more than 5.5 years ( 54 ).…”