During its second-quarter earnings report, Cambridge, Mass.-based TCR2 Therapeutics Inc. touted the start of a phase I/II trial with TC-210 to treat patients with mesothelin-positive tumors of various types, and interest continues to grow in the company's approach.

TCR2's T-cell receptor (TCR) Fusion Construct T cells, called TRuC-T cells, specifically recognize and kill cancer cells by harnessing signaling from the entire TCR, independent of human leukocyte antigens. In preclinical studies, TRuC-Ts have shown superior antitumor activity compared to chimeric antigen receptor (CAR) T cells with lower levels of cytokine release. TC-210 is the leading TRuC-T candidate, and is being tested against non-small-cell lung cancer, ovarian cancer, malignant pleural/peritoneal mesothelioma (MPM) or cholangiocarcinoma.

The company wants to outdo first-generation CAR T therapies, and maybe it can, since TRuC-Ts have all the TCR attributes of the natural setup. "We find the platform very promising, but the clinical programs are too early to call," as Roth analyst Tony Butler put the matter when he started coverage of TCR2 in late May with a neutral rating. "Preclinical investigations of engineered TRuC T-cells suggest that activation and signaling through the complete TCR allows for superior T-cell performance against tumors compared to CAR-T cells. Further, such constructs allow TRuCs to functionally kill solid tumors in vivo in contrast to CAR-T cells." Fewer side effects may turn up, too, in Butler's view.

At the end of July, TCR2 made public a cooperative research and development agreement with the National Cancer Institute (NCI) to collaborate on the use of TRuC-Ts in cancer. Under the terms, the NCI will recruit and treat patients in the phase I/II trial and conduct translational/biomarker studies to get a better grip on the pharmacodynamics of TC-210 in humans. The pact represents "a continued trend of recognition from the scientific community on the novel mechanism and promise of TCR2's platform," wrote SVB Leerink analyst Jonathan Chang.

The company's hardly alone in the mesothelin-positive cancer space. Atara Biotherapeutics Inc., of South San Francisco, has licensed an anti-mesothelin CAR T-cell program from Memorial Sloan Kettering Cancer Center (MSKCC). Encouraging phase I data for intrapleurally administered cells in combination with anti-PD-1 Keytruda (pembrolizumab, Merck & Co. Inc.) were presented at the American Society of Clinical Oncology meeting in Chicago in June. At the time, an overall response rate of more than 48% was reported in mesothelioma. Based upon the emerging data, Atara intends to push a next-generation autologous mesothelin product into the clinic next year. That product will incorporate the same single-chain variable fragment (scFv) from the MSKCC trial, a 1XX signaling domain, and a PD-1-dominant negative receptor. Atara plans to pursue both intrapleural and intravenous administration in mesothelioma and other mesothelin-positive tumors. The scFv is "something that we are learning from the first-generation CAR T development of our collaborators" at MSKCC, CEO Pascal Touchon said during an Aug. 8 conference call with investors on second-quarter earnings. "And that same scFv is being part of the construct of the next generation, with the new co-stimulatory domain that is aiming at having the right balance between expansion and persistence of the CAR Ts. Then, of course, we have added the PD-1-dominant negative receptor to have really a more physiological way of addressing the need to target PD-1 and make sure that we have enough activity of the cells once they are penetrated into the tumor."

Harpoon Therapeutics Inc., also of South San Francisco, said in April that it had dosed the first patient with mesothelin-targeting HPN-536 in a phase I trial initially focused on ovarian cancer. The compound is described as a 50-kD single polypeptide that contains three binding domains: to mesothelin, serum albumin and CD3. The phase 1/IIa trial is a multicenter, open-label experiment designed to evaluate the safety, tolerability, pharmacokinetics and activity of the drug in up to 80 patients with mesothelin-expressing cancers.

Swedish Orphan Biovitrum AB, of Stockholm, has NI-1801, an anti-CD47/mesothelin bispecific antibody at the preclinical stage being developed for a variety of solid tumors that express mesothelin. The compound came aboard in June, when Sobi expanded its deal with Geneva-based Novimmune SA by acquiring Gamifant (emapalumab) and all related assets. Sobi also took in all emapalumab employees involved in clinical and biopharmaceutical development. Gamifant is marketed for treating pediatric and adult patients with the life-threatening inflammatory condition primary hemophagocytic lymphohistiocytosis who have refractory, recurrent or progressive disease or intolerance to conventional therapies. It's the first and only FDA-approved therapy for the indication. (See BioWorld, June 13, 2019.)

UPenn shortfall 'positive' for TCR2

Though early stage, TCR2 is coming on strong with TRuCs. Phase I data from the University of Pennsylvania (UPenn) testing a mesothelin CAR T prospect in patients with MPM, ovarian cancer and pancreatic ductal adenocarcinoma turned up not-so-great efficacy, achieving the best response in stable disease (SD, 73%). "We think there's positive read-through to TC-210, since the vast majority of the deficiencies highlighted by the UPenn investigators have been circumvented in the TC-210 phase I/II trial," wrote Jefferies analyst Biren Amin.

Data published in Molecular Therapy came from an experiment in refractory patients who had failed five previous lines of therapy. The treatment was well-tolerated with one dose-limiting toxicity (grade 4 sepsis), but the best overall response was SD in 11 of 15 patients at 28 days and median progression-free survival of just over two months. "A closer look revealed responses were transient with most lesions remaining unresponsive," Amin noted. "Particularly, patients with pancreatic cancer showed the greatest percentage of lesions progressing within 28 days, raising concerns [about whether] mesothelin is a validated therapeutic target in this tumor type. The suboptimal efficacy was correlated with short persistence (< 28 days) of mesothelin CAR T-cells, presumably due to murine-derived scFv-induced immune elimination. To address this possibility, another phase I trial evaluating a fully human scFv-incorporated mesothelin-CAR in [the] same indications has been initiated" at the university, he said. "However, this study showed concerning safety signals where two out of nine patients experienced grade 4/5 respiratory toxicity."

TCR2, though, is deploying a fully human mesothelin scFv which could mean better persistence, and screening for mesothelin expression, which the UPenn researchers did not require. It's also testing various lymphodepletion regimens to optimize before starting the phase II portion of the trial. TC-210 has been optimized for higher CXCR3 expression as well, and pancreatic cancer patients are excluded from the study.


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