Tumor-infiltrating lymphocytes show ‘provocative’ response rates in advanced melanoma
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More than half of patients with heavily pretreated melanoma responded to therapy with unselected tumor-infiltrating lymphocytes, according to results of a retrospective study.
Researchers derived the data, presented during the virtual American Association for Cancer Research Annual Meeting, from a single-center evaluation of tumor-infiltrating lymphocytes (TILs) administered to patients with late-stage melanoma via a compassionate use protocol.
The study started more than a decade ago and built upon previous TIL research conducted by the NCI, according to Robert E. Hawkins, MD, PhD, chief strategy advisor for Instil Bio and honorary professor of medical oncology at University of Manchester.
Hawkins and colleagues sought to determine the feasibility of providing TIL therapy outside the NCI — at an academic medical center —and to patients with disease progression after all other standard therapies.
“We have a slightly different manufacturing process than what the NCI uses,” he told Healio. “There were distinct regulations around manufacturing in Europe that required some changes from the NCI process.”
The Instil Bio process used autologous unselected TILs from digested tumor tissue that were produced under a manufacturing specials license issued by the U.K.’s Medicines and Healthcare products Regulatory Agency. The shorter manufacturing process, compared with other methods, enables the final TIL product to contain the widest spectrum of T-cell receptor reactivity possible, according to Hawkins.
The study included 21 patients (median age, 45 years; range, 16-68; 71% men), all of whom had stage IV relapsed or refractory advanced cutaneous melanoma.
Patients received a median three (range, 1-9) lines of previous therapy, and 91% had received an immune checkpoint inhibitor. Fifty-two percent of patients had BRAF-mutant disease, and all of them previously received BRAF and/or MEK inhibitors.
All patients initially were hospitalized for study treatment, which consisted of nonmyeloablative lymphodepletion with 60 mg/kg cyclophosphamide daily for 2 days and 25 mg/m2 fludarabine daily for 5 days followed by TIL infusion and high-dose interleukin-2 (600,000 IU/kg to 720,000 IU/kg) to promote TIL activity.
Patients received a median 32 × 109 (range, 8 × 109 to 63 × 109) TIL cells and a median eight (range, 4-11) doses of IL-2.
Researchers evaluated efficacy among 15 patients based on locally assessed CT/MRI per RECIST version 1.1 and among the remaining six patients based on non-RECIST imaging, such as PET, and clinical monitoring.
Median follow-up was 52.2 months, with a data cutoff date of Dec. 31, 2019.
Safety results showed all patients experienced at least one treatment-related adverse event, including thrombocytopenia (62%), pyrexia (57%) and rigors (43%). Researchers observed no treatment-related deaths.
"All the toxicity we have seen in our study is consistent with what has been reported in other clinical trials of TILs in that toxicity is related to preconditioning chemotherapy and the administration of IL-2,” Zachary J. Roberts, MD, PhD, chief medical officer for Instil Bio, told Healio. “These toxicities tended to be self-limited and managed supportively. Some patients spent a few days in the hospital and then were discharged with no further toxicities observed.”
The overall response rate among 15 imaging-evaluable patients was 53%, with a 67% ORR for the entire study population. Two patients (13%) in the imaging-evaluable group had a complete response to therapy, compared with four (19%) in the entire study population.
Three imaging-evaluable patients (20%) had stable disease, for an overall disease control rate of 73%.
Median OS was 21.3 months (95% CI, 6.8 to not estimable) for the entire study population and not yet reached for patients who had a complete or partial response to therapy.
Five patients (24%) had ongoing responses to therapy more than 30 months after TIL infusion, and all patients who had a complete response to therapy were alive and disease-free as of the data cutoff date.
Although it is too early to declare their TIL process more effective than other approaches, which would require further comparison studies, “our response rates are provocative,” Roberts told Healio.
“Part of what makes our process exciting and relevant in this era of added attention on TILs is its flexibility,” he said. “It's a measurably different process that allows us the potential to rapidly scale our clinical trial development program. If we end up achieving FDA approval for this therapy, our approach will end up significantly improving logistics in the commercial setting.”
Hawkins said the response rates are clinically meaningful compared with a 2019 systematic review and meta-analysis that showed a 41% ORR for TILs in this patient population.
“There was a very high response rate, with some complete remissions,” he said, adding that the treatment appears to be durable among those who had a complete response, whereas many other patients achieved stable disease with reduced tumor burden.
“The therapy improves patients' quality of life and can be quite durable,” Hawkins said. “Overall, it is very beneficial to patients."
Reference:
Danfi U, et al. Ann Oncol. 2019;doi:10.1093/annonc/mdz398.
Perspective
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Lisa Butterfield, PhD
It is very good to see positive data on total, unselected TIL efficacy in melanoma — even after checkpoint blockade and other therapies — among patients with late-stage disease. Although this therapy has been in the investigational armory for melanoma for a long time, the breadth of specificities in such products is now better understood. I look forward to mechanistic studies of the products and the patient specimens.
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Jason Bock, PhD
As growing attention focuses on the TIL field as a viable commercial modality for solid tumors, Hawkins and Instil Bio have taken a novel approach. Whereas many TIL development programs focus on selecting a subset of TILs, this group has taken an orthogonal approach of ensuring a wide and unbiased population of TILs. They then can focus on shortening the manufacturing time.
Finding the optimal balance between T-cell receptor diversity/specificity, tumor microenvironment armoring, T-cell fitness and manufacturing robustness and duration will be of intense focus as TIL therapy moves into the mainstream. Different companies and academic medical institutes are taking a variety of approaches. Through well-controlled studies coupling reliable outcome data with advances in correlate analysis, not only will the TIL field generate commercially viable therapeutics in solid tumors, but also it may serve as a lens to reveal the biology of T-cell/tumor equilibrium. The next several AACR meetings will surely be filled with insights from innovative TIL studies.
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Kim Margolin, MD
Although this small, retrospective report includes few patients and limited follow-up, the results suggest a favorable survival plateau resulting from the strategy.
Any attempt to dissect the elements of the program and attribute the benefits to less than the entire regimen must be avoided, as patients had previously received immune checkpoint blockade and, when indicated, MAP kinase inhibitors; the lymphodepleting agents are essentially inactive against melanoma; and six doses of high-dose IL-2 also will not provide remissions in half of the treated patients. In addition to the patient, tumor and therapy details that require further investigation, it will be important to study and then potentially introduce critical enhancements of cell therapy. Among the enhancements are recruitment of the maximum number of highly active effector cells to the tumor and inhibition of suppressive elements in the immune tumor microenvironment. Strategies to prevent exhaustion that prolong the survival and enhance the function of these therapeutic TIL cells also will be important.
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Hawkins RE, et al. Abstract LB-150. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.
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