TCR T-cell therapy induces response in solid cancers
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Half of patients with relapsed or refractory solid tumors achieved objective response to an infusion of IMA203, according to study results presented at Society for the Immunotherapy of Cancer Annual Meeting.
None of the patients treated thus far experienced high-grade neurotoxicity or cytokine release syndrome.
IMA203 (ACTengine, Immatics) is an autologous T-cell receptor (TCR) T-cell therapy that is gene-edited to express a T-cell receptor that recognizes preferentially expressed antigen in melanoma (PRAME) protein in tumor cells.
“We’ve seen prolonged disease stabilization in responses by some patients but not all,” Martin Wermke, MD, head of the early clinical trial unit of National Center for Tumor Diseases at University Hospital Carl Gustav Carus in Dresden, Germany, said during a presentation. “We will need for the data to mature to be sure that sustainable responses are being obtained with this type of drug.”
Some previous trials that evaluated TCR T-cell therapy for solid tumors were not optimized to match highly expressed tumor antigens with the proper TCRs, Wermke said.
He called IMA203 “special” in this respect because the manufacturer uses a proprietary platform to identify promising T-cell receptors to target a patient’s tumors. This type of targeting may account for the relatively high response rate conferred by IMA203 compared with previous investigational cell therapies for solid tumors, he said.
“It's really about selecting the right patients and the right T-cell receptor,” he said.
IMA203 is being evaluated as part of a first-in-human multicenter phase 1 trial that includes patients who are HLA-A*02-positive and have PRAME-positive advanced or metastatic solid tumors.
Safety as determined by treatment-related adverse events served as the study’s primary objective. T-cell persistence and tumor response per RECIST version 1.1 served as secondary objectives.
Study participants underwent lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (500 mg/m2) prior to infusion with IMA203, followed by a 10-day regimen of low-dose interleukin-2 (1 million IU per day).
Nineteen patients (mean age, 50 years; range, 18-65) received the investigational therapy at one of four escalating dose levels, ranging from 0.04-0.06 × 109/m2 to 1.2 × 109/m2 TCR T cells.
The efficacy-evaluable population consisted of 16 patients who underwent at least one post-treatment scan. Patients had received a median four (range, 2-8) prior lines of therapy for PRAME-positive cancers, the most common of which include synovial sarcoma (n = 4), head and neck cancer (n = 3), cutaneous malignant melanoma (n = 3) and uveal melanoma (n = 2).
Eight patients (50%) achieved objective response — all partial responses — and 15 (93.75%) exhibited stable disease.
“Responses were seen exclusively from dose level 2 onward so, if you consider only those patients receiving meaningful cell doses, responses were seen in eight of 13 patients, equaling a response rate of 63%,” Wermke said.
Researchers observed responses “across multiple solid cancers,” Wermke added. These included synovial sarcoma (n = 3), melanoma (n = 3), uveal melanoma (n = 1), and head and neck cancer (n = 1).
"In the peripheral blood, we observed rapid, robust and persistent engraftment of TCR-modified T cells,” Wermke said. “More importantly, we were able to show tissue infiltration of TCR-modified T cells in all patients who submitted evaluable specimens. There was a significant difference between responders and nonresponders, with the former showing higher TCR-modified T-cell infiltration in tumor tissue.”
Sixteen (84.2%) of the 19 patients who received IMA203 infusion developed CRS; however, no cases of high-grade CRS occurred. Four patients (21%) experienced immune effector cell-associated neurotoxicity syndrome, with no high-grade cases among the study population.
Researchers attributed most grade 3 or greater treatment-related toxicities to lymphodepletion chemotherapy. They included neutropenia (78.9%), lymphopenia (73.7%) and leukopenia (57.9%). This led to a greater susceptibility to subsequent infections, Wermke said.
One patient from the second dose level group (0.12-0.18 × 109/m2 TCR T cells) developed a dose-limiting toxicity.
“IMA203 has a transient and manageable adverse event profile, as can be expected for a cellular therapy product,” Wermke said. “We have not seen any signs of autoreactivity in patients treated so far.”
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Wermke M, et al. Abstract 959. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 10-14, 2021; Washington, DC.
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