Autologous TIL Therapy Plus Pembrolizumab Under Exploration in PD-L1–Resistant Advanced HNSCC

The addition of TBio-4101, a novel cell therapy comprising autologous selected and expanded tumor-infiltrating lymphocytes (TILs), to pembrolizumab (Keytruda) is being investigated as a potential therapeutic option in patients with PD-(L)1 inhibitor–resistant, advanced head and neck squamous cell carcinoma (HNSCC) as part of an ongoing, phase 1b study (NCT06236425).^1,2

The primary end points of the study are to examine the safety and tolerability of TBio-4101 through assessment of the frequency, duration, and severity of treatment-emergent adverse effects (TEAEs).

“The [goal of] this trial is essentially to provide a readily available second-line treatment for patients whose [head and neck] cancers progress on standard-of-care [SOC] treatments for their recurrent/metastatic disease,” first author Kedar Kirtane, MD, said in an interview with OncLive®. Kirtane is an assistant member in the Department of Head and Neck-Endocrine Oncology and medical director of Solid Tumor Cellular Therapy at Moffitt Cancer Center in Tampa, Florida.

Novel strategies to improve treatment activity represent a critical and unmet need for patients with recurrent or metastatic HNSCC. This patient population has limited treatment options in the first line and beyond, and accordingly, has poor prognosis.

“As of now, patients with recurrent or metastatic HNSCC really only have one SOC, and that’s pembrolizumab plus or minus chemotherapy,” Kirtane stated in the interview. “Unfortunately, the majority of those patients experience progression of their cancer despite that treatment and, as of now, we don’t have anything in the second line that would meaningfully take care of these patients.”

Although cell therapies can provide a more personalized treatment approach for patients compared with standard immune checkpoint inhibitors, cell therapies have traditionally depended on bulk products that may not effectively select for a tumor-reactive T-cell population.

“The particular rationale is to use a TIL therapy,” Kirtane said. “This was initially approved in the United States for patients with melanoma earlier in 2024, [and now] we’re trying to apply a TIL for patients with recurrent metastatic HNSCC…A TIL product [finds] those lymphocytes that have already tracked to the tumor, recharges them in a way that makes sense, and finds lymphocytes that are hopefully going to affect change in the tumor [so they can be] given back to those patients who truly need them.”

The manufacturing technique used to produce TBio-4101 employs single-cell sorting of patient-specific neoepitope-reactive TILs that may address immunologically “cold” tumors. This method enriches polyclonal, polyfunctional, tumor-reactive T cells with an endogenous neoantigen-reactive T-cell receptor repertoire capable of targeting multiple tumor antigens. By significantly reducing non–tumor-reactive bystander T cells, which usually constitute at least 90% of bulk TILs and can reduce treatment efficacy through product dilution, this approach may enhance the potency of the therapy.

Building on the clinically successful NCI selection and enrichment strategies, TBio-4101 is optimized to identify and potentially enrich the percentage of tumor-reactive CD8- and CD4-positive T cells to over 70%.

“This product is unique in the sense that what we do is we also combine it with an apheresis to select out unique lymphocytes that are more likely to cause tumor reduction,” Kirtane explained. “This is in contrast to other TIL products, which don’t necessarily separate out [T cells] that are known to work and can work vs the ones that may not work as effectively.”

This open-label, single-center trial is enrolling patients between 18 and 75 years of age with pathological confirmed, recurrent, unresectable or metastatic HNSCC who progressed on pembrolizumab with or without chemotherapy. An ECOG performance status of 0 or 1, at least 1 cm3 of viable tissue for resection and TIL generation, and at least 1 remaining target tumor for response assessment were also required.

Notably, patients with nasopharyngeal and nasal cavity carcinomas were not eligible for enrollment. Other exclusion criteria included prior treatment for metastatic disease; prior treatment with a PD-(L)1 inhibitor; known active central nervous system metastases and/or carcinomatous meningitis; a primary or acquired immunodeficiency disorder; and prior cell therapy or organ transplant.

Patients will undergo tumor harvest for TILs followed by apheresis to collect monocytes, followed by first-line SOC treatment of pembrolizumab with or without chemotherapy.

TBio-4101 will be administered after 5 days of preconditioning with nonmyeloablative lymphodepletion, after which patients will receive no more than 6 doses of intravenous bolus interleukin-2 every 8 hours and 200 or 400 mg of pembrolizumab every 3 or 6 weeks until disease progression. A total of 15 patients are targeted for enrollment.

Whole exome and RNA sequencing of tumor and germline samples will be used to identify patient-specific neoepitopes, creating a peptide pool of potential tumor-specific mutations. Next, monocytes isolated from apheresis will be differentiated into dendritic cells, pulsed with neoepitope peptides, and co-cultured with TILs. Tumor-reactive T cells will then be selectively activated based on upregulation of activation markers before being expanded in culture.

Secondary end points include overall response rate according to both RECIST 1.1 and iRECIST criteria; durable response rate within 12 months and lasting at least 6 months; duration of response; disease control rate; and feasibility.

“Right now, our primary outcome is safety, but we also want to have some preliminary efficacy analyses,” Kirtane concluded. “Hopefully, we [will see] some good response rates in patients who require these treatments in the second line.”

Disclosures: Dr Kirtane reported the following disclosures: a leadership role with MyCareGorithm; consulting or advisory roles with MyCareGorithm; stock or other ownership interests with Agenus, Oncternal Therapeutics, Seagen and Veru; and expenses related to travel and accommodations from A2Bio.

References

1. Kirtane K, Verdon I, Hall M, et al. Alliance A022101: A phase 1b study of tbio-4101 (autologous selected and expanded tumor-infiltrating lymphocytes [TILs]) with pembrolizumab in patients with anti-PD-1–resistant, advanced head and neck squamous cell carcinoma (aHNSCC). J Clin Oncol. 2023;41(suppl 16):TPS6115. 10.1200/JCO.2024.42.16_suppl.TPS6115
2. Tbio-4101 and pembro wi/ or w/o chemo in recurrent/metastatic HNSCC. ClinicalTrials.gov. Updated June 28, 2024. Accessed July 18, 2024. https://clinicaltrials.gov/study/NCT06236425