Treatment with unselected autologous tumor-infiltrating lymphocytes (TILs) showed early clinical efficacy among patients with advanced melanoma, according to results presented by Hawkins et al during week 1 of the virtual American Association for Cancer Research (AACR) Annual Meeting 2021 (Abstract LB150).
“Despite treatment advances in melanoma, only a minority of patients with advanced disease experience long-term survival, and those with progression on standard therapies have limited treatment options,” said study author Robert Hawkins, MD, PhD, Chief Strategy Advisor at Instil Bio Inc and Honorary Professor/Consultant in Medical Oncology at the University of Manchester and The Christie Hospital. “Most patients with melanoma now receive immune checkpoint inhibitors or targeted therapies as part of their front-line treatment, but there is a need for efficacious therapies when such patients experience disease progression.”
More on TILs
In previously described TIL treatments, T cells have been harvested from fragments of a patient’s tumor only after demonstrating antitumor reactivity. These selected T cells are then expanded ex vivo and infused back into the lymphodepleted patient.
Dr. Hawkins and colleagues, however, use a slightly different approach. Instead of only expanding the TILs from fragments with measurable reactivity against the tumor, they digest the entire tumor and then harvest and expand all the TILs that were contained in the resected specimen. This process not only shortens the lengthy manufacturing process associated with first-generation TIL products, but also allows the broadest spectrum of T-cell receptor (TCR) reactivity possible to be contained in the final product. By eliminating the selection step, additional neoantigen-reactive T cells that evaded selection for reasons other than TCR specificity may be captured and infused, Dr. Hawkins explained.
“Prior studies have indicated that younger TILs made with shorter manufacturing times are more reactive against a patient’s cancer,” he said. “Our unselected process is both roughly half the duration of previously described methods as well as more inclusive, resulting in younger and fitter TILs with potentially a larger spectrum of reactivity.”
Because the manufacturing process is more efficient than selection-based techniques, it may be more beneficial than previously described TIL methods among patients with advanced metastatic disease, who require timely treatment options, Dr. Hawkins added.
Study Methods
Dr. Hawkins and colleagues treated 21 patients with high-risk metastatic melanoma on a compassionate use basis. Over 90% of patients had previously received treatment with an immune checkpoint inhibitor, and over 50% of patients had previously received targeted therapy, such as treatment with a BRAF inhibitor with or without a MEK inhibitor. A small piece of each patient’s metastatic tumor was removed and digested to release all of the TILs present in the specimen at the time of resection. These digests can also be frozen and stored for later use. After manufacturing was complete, patients were treated with lymphodepleting chemotherapy followed by the TIL product and high-dose interleukin-2 (IL-2), a cytokine that helps to support the in vivo growth and activity of the TILs.
Of the 21 patients, 15 were evaluated via serial computed tomography (CT) or magnetic resonance imaging (MRI) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; the remaining six patients were evaluated using non-RECIST imaging (eg, with positron-emission tomography [PET]) and clinical monitoring. The median follow-up time was 52.2 months.
Results
Among the imaging-evaluable patients, the objective response rate was 53%, with approximately 13% of patients experiencing a complete response (two patients). The disease control rate was 73%, including three patients (20%) experiencing stable disease. Among the patients followed using non-RECIST imaging, durable responses were observed, including two with complete responses who remain in remission (for more than 4 and 7 years, respectively). Cumulatively, the objective response rate for all treated patients was 67%, with 19% (4 of 21) experiencing a complete response.
Adverse events associated with the TIL regimen were consistent with those observed in other trials of TILs for melanoma. They included transient low blood counts attributed to lymphodepleting chemotherapy, as well as IL-2–related fever, tachycardia, rigors, and other symptoms. These side effects were managed supportively and resolved, Dr. Hawkins said.
“We were encouraged by these results, as they compare well to historical outcomes with TIL therapies in patients with advanced melanoma,” said study author Zachary Roberts, MD, PhD, Chief Medical Officer at Instil Bio. A recent meta-analysis published by Dafni et al in Annals of Oncology evaluating clinical trials of TIL therapies in this patient population had an estimated objective response rate of 41%, with a complete response rate of 12%, Dr. Roberts noted.
This was a small series from a single center testing unselected autologous TIL for compassionate use treatment, representing a limitation of the study. “Prospective clinical trials are warranted and planned to validate our results,” said Dr. Roberts.
Disclosure: This study was a compassionate use program, and patient treatment was funded through a number of sources, including the United Kingdom National Health Service or private health insurance. Initial funding to set up the cell therapy manufacturing facility was provided through the University of Manchester. Data analysis was conducted by Instil Bio Inc. Drs. Hawkins and Roberts are employed by and have equity ownership in Instil Bio Inc. For full disclosures of the study authors, visit abstractsonline.com.
