Abstract
A natural immune response was generated to somatic mutations in metastatic breast cancer patients.
Major Finding: A natural immune response was generated to somatic mutations in metastatic breast cancer patients.
Concept: This phase II pilot trial combined pembrolizumab and adoptive transfer of autologous neoantigen-reactive T cells.
Impact: Objective responses were demonstrated in this highly personalized approach and suggest the need for further study.
Use of immune checkpoint blockade therapy in metastatic breast cancer (mBrCa) has only a modest effect on disease progression, but adoptive cell transfer (ACT) of autologous tumor-infiltrating lymphocytes (TIL) has demonstrated a durable objective response in patients with metastatic disease, including mBrCa. Zacharakis and colleagues investigated the immunogenicity of somatic mutations and the use of neoantigen-reactive TILs as a potential treatment option in a phase II pilot trial with 42 patients with treatment-refractory mBrCa who underwent surgical resection of one or more metastatic lesions. TILs were isolated and grown from all patients, and upon screening for neoantigen-reactive TILs, 28 out of the 42 patients contained TILs that were able to recognize at least one neoantigen. Of all somatic mutations tested, 2.3% were immunogenic, and most were unique among patients, with only mutations in TP53 occurring in more than one patient. Thirteen patients showed suitable mutation recognition to undergo potential adoptive transfer as part of the pilot phase II trial, and six clinically eligible patients were treated with ACT and pembrolizumab (a PD-1 inhibitor). The primary endpoint for the clinical study was objective response rate, and three patients had an observed objective tumor response, with one patient experiencing a complete regression that is ongoing at 66 months. The second patient demonstrated a partial response lasting for 10 months before new nodules appeared, and sequencing of these nodules revealed mutations affecting nine of the 11 neoantigens. The third patient also experienced a partial response, lasting for 6 months, with copy-number analysis indicating loss of heterozygosity of the HLA locus and a potential antigen presentation defect upon regression. This study identified somatic mutation–specific T cells and neoantigens encoded by a broad range of genes that were validated through ex vivo functional assays, and these interim results suggest the critical need for expanded accrual to continue exploration of the clinical response to this treatment strategy.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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