On August 23, 2022 Immatics N.V. (NASDAQ: IMTX, "Immatics"), a clinical-stage biopharmaceutical company active in the discovery and development of T cell-redirecting cancer immunotherapies, reported the treatment of the first patient in its Phase 1b expansion cohort C (NCT03686124) evaluating IMA203CD8, the company’s 2nd generation TCR-T monotherapy approach where a proprietary CD8αβ co-receptor is added to PRAME-specific IMA203 T cells (Press release, Immatics, AUG 23, 2022, View Source [SID1234618568]). The CD8 co-receptor plays an important role during T cell antigen recognition and T cell activation, enabling the effective engagement of CD8 and CD4 T cells in the anti-tumor response. The 2nd generation TCR-T IMA203CD8 aims to further enhance depth and durability of anti-tumor responses and clinical outcomes of TCR-T targeting PRAME in patients with solid cancers. PRAME is highly prevalent across several indications thereby supporting the program’s potential to reach a broad patient population.
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"IMA203CD8’s unique mode of action has been validated by preclinical data presented at SITC (Free SITC Whitepaper) last year, which demonstrated sustained suppression of tumor growth in serial killing experiments. With the initiation of the IMA203CD8 cohort, we can now test to what extent the interplay of engineered CD8 and CD4 T cells enhances anti-tumor activity in the clinical setting," said Dr. Cedrik Britten, M.D., Chief Medical Officer at Immatics. "Today’s milestone brings us closer to our goal of achieving long-lasting responses for a broad range of cancer patients having solid tumors that express PRAME."
The importance of CD4 T cells for the duration of responses has been demonstrated by Immatics in preclinical assays where IMA203CD8 showed enhanced potency and prolonged anti-tumor activity compared to IMA203 alone. These findings are in line with a growing body of literature from CD19 CAR-T cells in hematological cancers that suggest a relevant role of engineered CD4 T cells in maintaining durable anti-tumor responses over a long period. Immatics’ proprietary lentiviral vector enables CD4 and CD8 T cells to be engineered with the PRAME-specific IMA203 TCR and a CD8αβ construct. In the preclinical studies, this approach showed functional superiority over multiple other CD8 constructs in conjunction with the PRAME-specific IMA203 TCR. Immatics has successfully developed a proprietary 4-in-1 vector that includes both IMA203 TCRα and TCRβ as well as CD8α and CD8β chains while maintaining a high transduction rate, circumventing the challenges associated with increasing the lentiviral vector payload.
The IMA203CD8 Phase 1b dose expansion cohort is expected to enroll up to 24 patients with different types of solid tumors across several clinical trial sites in the U.S. and in Germany. Following personalized manufacturing and lymphodepletion, patients will receive a single dose of IMA203CD8. Initially, 3 patients will be treated at a dose level 3 (DL3, up to 0.48 billion total transduced T cells per m² body surface area) before patient treatment at the provisional recommended Phase 2 dose, DL4 (up to 1.2 billion total transduced cells per m² body surface area). The primary objective of this Phase 1b cohort is to evaluate the safety profile of IMA203CD8. Secondary objectives include evaluating initial anti-tumor and biological activity.
The 2nd generation TCR-T IMA203CD8 is part of Immatics’ strategy to realize the full clinical potential of IMA203 TCR-T targeting PRAME. This strategy includes three Phase 1b expansion cohorts, which have all been initiated during the first half of 2022 and build on the promising early clinical results during the company’s Phase 1a trial. Interim data showed a 50% objective response rate (8/16 patients) across several solid tumor indications including melanoma, head and neck cancer, uveal melanoma and synovial sarcoma.
Cohort A – IMA203 as monotherapy at the provisional, recommended Phase 2 dose (RP2D) plus exploration of a higher dose level DL5 (up to 4.7 billion transduced CD8 T cells per m² body surface area)
Cohort B – IMA203 in combination with an immune checkpoint inhibitor, Opdivo (nivolumab)
Cohort C – IMA203CD8, a 2nd generation monotherapy in which IMA203 is co-transduced with a CD8 co-receptor
Each Phase 1b expansion cohort is designed to evaluate the observed objective response rate, demonstrate durability of response and provide the basis for entering registration trials. The next data readout for the IMA203 monotherapy cohort at RP2D is expected during 2H 2022 and an initial data readout for Cohort B and Cohort C is planned for YE2022.
About IMA203CD8 and target PRAME
ACTengine IMA203CD8 T cells are directed against an HLA-A*02-presented peptide derived from preferentially expressed antigen in melanoma (PRAME), a protein frequently expressed in a large variety of solid cancers thereby supporting the programs’ potential to address a broad cancer patient population. Immatics’ PRAME peptide is present at a high copy number per tumor cell and is homogenously and specifically expressed in tumor tissue. The peptide has been identified and characterized by Immatics’ proprietary mass spectrometry-based target discovery platform XPRESIDENT. Through its proprietary TCR discovery and engineering platform XCEPTOR, Immatics has generated a highly specific T cell receptor (TCR) against this target which is engineered into CD8 and CD4 T cells alongside a proprietary CD8αβ co-receptor for its 2nd generation TCR-based cell therapy approach, ACTengine IMA203CD8. In preclinical studies, Immatics’ proprietary CD8αβ construct showed functional superiority over multiple other CD8 constructs in conjunction with the PRAME-specific IMA203 TCR.
About ACTengine
ACTengine is a personalized cell therapy approach for patients with advanced solid tumors. The patient’s own T cells are genetically engineered to express a novel, proprietary TCR directed against a defined cancer target. The modified T cells are then reinfused into the patient to attack the tumor. The approach is also known as TCR-engineered cell therapy (TCR-T). All Immatics’ ACTengine product candidates can be rapidly manufactured utilizing a proprietary manufacturing process designed to enhance T cell engraftment and persistence in vivo.
The ACTengine T cell products are manufactured at the Evelyn H. Griffin Stem Cell Therapeutics Research Laboratory in collaboration with UTHealth.