Precision Treatment With TIL Shows Promise in Metastatic Breast Cancer

Targeted immunotherapy that utilizes a patient’s own tumor-infiltrating lymphocytes (TIL) may be added to the treatment armamentarium for individuals with metastatic breast cancer with repeated treatment failures, according to a new Journal of Clinical Oncology study.

In particular, patients with hormone receptor (HR)-positive cancers may benefit from the personalized treatment, as “it’s popular dogma that HR-positive breast cancers are not capable of provoking an immune response and are not susceptible to immunotherapy,” said lead author Steven A. Rosenberg, MD, PhD, chief of the Surgery Branch in National Cancer Institute's Center for Cancer Research, in a statement announcing the findings.

At present, the effectiveness of TIL against breast cancers is not 100% solidified because these types of cancers have fewer mutation-produced neoantigens, or surface proteins, that TIL recognize and target on tumors, the statement read.

Forty-two patients (median age, 46 [range 35-67] years) with refractory metastatic breast cancer were recruited for the ongoing phase 2 study. Mutations from their tumor samples were analyzed via whole-genome sequencing, after which TIL were isolated and tested against the mutations’ neoantigens. Most had stage II to IV disease, 43% of tumors were HR positive/ human epidermal growth factor receptor 2 negative, and 38% had triple-negative breast cancer. Median prior treatment consisted of 4 (range, 1-10) lines of therapy.

The primary end point was objective response measured using Response Evaluation Criteria in Solid Tumors 1.0.

A median 112 (range, 6-563) nonsynonymous mutations were identified overall per patient following surgical tumor resection; this was not linked to clinical receptor status, tumor site, or presence/or absence of known deleterious BRCA germline variants. In addition, just over two-thirds of the cohort (67%; 28 patients) had at least 1 mutation recognized by TIL; among this group, there were a median 3 (range, 1-11) neoantigens per patient.

The full study cohort had undergone surgical tumor resection, with the tissue used to isolate TIL cultures, identify exomic nonsynonymous mutations, and screened for neoantigen reactivity.

Among the smaller group of 28 patients, 13 were identified as having robust reactivity. Six were identified as candidates for adoptive cell transfer (ACT) of their autologous TIL following nonmyelobaltive lymphodepleting chemotherapy consisting of 60-mg/kg daily cyclophosphamide on days –7 and –6 and 25-mg/m² daily fludarabine from day –7 through day –3. All also received a short course of treatment with pembrolizumab 2 days before ACT, which continued with 3 doses delivered every 3 weeks when appropriate.

“The total number of infused cells ranged from 3.06e10 to 1.04e11 (median, 6.00e10) per patient and were predominantly CD4+ T cells (CD4+ median, 56% [range, 46%-97%]; CD8+ median, 37.5% [range, 2%-52%]),” the authors wrote. “The frequency of the neoantigen-reactive T cells of the infused TIL ranged from 10.4% to 75.2%, as estimated by TCR sequencing.”

Three patients had an objective tumor response: one patient with metastatic liver, lymph node, and mediastinum tumors has ongoing complete tumor regression and 2 had partial responses of 6 and 10 months.

When discussing the strength of their findings, the authors highlighted their use of ex vivo functional assays for precise identification and validation of neoantigens instead of predictive algorithms to characterize TIL and immunogenicity. Still, they recognize that these are interim results and that the patient cohort was too small “to address potential correlates of response, including the number and abundance of neoantigen reactivities.”

Future steps will include additional patient recruitment to continue to explore this targeted approach among patients with metastatic breast cancer.

“Completion of the cohort is critical to evaluate the efficacy, as well as the challenges, of this highly personalized treatment against metastatic breast cancer,” they concluded.

Reference

Zacharakis N, Huq LM, Seitter SJ, et al. Breast cancers are immunogenic: immunologic analyses and a phase 2 pilot clinical trial using mutation-reactive autologous lymphocytes. J Clin Oncol. Published online February 1, 2022. doi:10.1200/JCO.21.02170