Personalized TCR Therapy Safe, Feasible in First-in-Human Trial

PACT Pharma’s NeoTCR-P1, an investigational personalized adoptive T-cell Receptor (TCR) therapy that is intended to target neo-antigens specific to patients’ own tumors, showed promising safety and proof-of-concept in patients with solid tumors in data from a phase 1a/b clinical trial (NCT03970382) presented at the Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting, November 8-12, 2022, in Boston, Massachusetts.

NeoTCR-P1 consists of autologous cells with TCRs that recognize patient-specific neoantigens. Non-viral precision gene editing is used to knock out endogenous TCRs and knock-in the best patient-specific neoTCRs, which are selected with a proprietary algorithm. Proof-of-concept of the screening and manufacturing process was demonstrated in the trial, and the cell product additionally showed ability to travel to tumors after infusion into patients. Among the 16 patients treated in the trial, 5 showed stable disease after treatment.

"Our algorithm takes into account the activation status of the T-cell that we isolated the TCR from, the TCR functionality, of course, and the neo-epitope truncality and expression, and also HLA diversity,” Stefanie Mandl, PhD, chief scientific officer, PACT Pharma, explained during her presentation. “We've developed a completely non-viral precision genome engineering process for the engineering of our neo-TCR T-cells. This is a single step process, and we're using CRISPR editing to simultaneously knock-out the endogenous TCR and then knock-in the neo-TCR. And in that way, we generate a T-cell in which the neo-TCR is expressed from the endogenous promoter and regulated and expressed at normal levels.”

In terms of safety, the treatment was well-tolerated, with the majority of adverse events (AEs) being attributed to the conditioning chemotherapy regimen. Excepting a single patient who experienced a grade 1 case of cytokine release syndrome (CRS), there were no incidences of CRS among the treated patients. A grade 3 case of encephalopathy was experienced by a patient with non-small cell lung-cancer (NSCLC) who had existing and worsening brain metastasis, but resolved after steroid treatment. Other AEs greater than grade 3 that occurred in the treated patients included anemia, febrile neutropenia, pancytopenia, thrombocytopenia, lymphopenia, neutropenia, leukopenia, and herpes zoster infection. All 16 patients cleared the full dose-limiting toxicity window.

In total 187 patients signed informed consent for the trial, 88 patients were screened for TCRs, and 16 were dosed. Four of the 16 patients received NeoTCR-P1 along with IL-2, while the remaining 12 received NeoTCR-P1 alone. The ages of the patients who received treatment ranged from 35 to 69 (median, 47), and there were 10 male patients and 6 female patients included. Cancer types of the patients treated included microsatellite stable (MSS)-colorectal cancer (n=11), HR+ breast cancer (n=2), ovarian cancer (n=1), melanoma (n=1), and NSCLC (n=1). The patients had previously been treated with between 2 and 9 prior regimens of therapy (median, 5). End points for the trial included the feasibility of TCR discovery and manufacturing of a multi-TCR product using complete non-viral gene editing and the incidents and nature of AEs defined as DLTs. Secondary end points included the overall response rate, duration of response, progression-free survival, and overall survival. In addition, retrospective benchmarking comparing the TCRs in the study to TCRs used in other studies was conducted.

“The retrospective benchmarking to other TCRs that showed clinical signal was very important...,” Mandl added in response to an audience question about potential drivers for better responses. “We have in the beginning cast a very wide net for TCR potencies because there are data in the literature that show that the high affinity TCRs are exhausting faster, and then in chronic infection, for example, lower affinity TCRs become more dominant. This is not what we saw in our study. And we could do the perfect experiment where we had 3 different T-cells with different affinities in the same patient. And I can tell you, I would now go with higher affinity TCRs.”

REFERENCE

Mandl S. 1478 A phase I study of personalized adoptive TCR T cell therapy in patients with solid tumors: safety, efficacy, and T cell trafficking to tumors of non-virally gene edited T cells. Presented at: Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting November 8-12, 2022; Boston, Massachusetts.