Coming off a $44.5 million series A financing in late 2016, TCR2 Therapeutics Inc. snagged another $125 million in an oversubscribed series B financing to advance programs using its T-Cell Receptor Fusion Construct (TRuC) platform. (See BioWorld Today, Dec. 9, 2016.)

"The primary driver was the realization that we have a platform that can be applied to solid tumors as well as hematological malignancies," TCR2's CEO Garry Menzel told BioWorld of the reason for the high investor interest. He said raising more capital than the company had originally intended would provide "financial flexibility" to fund multiple programs through proof of concept, carrying the company into 2021.

The series B financing was co-led by 6 Dimensions Capital and Curative Ventures with existing investors – MPM Capital, F2 Ventures and Cathay Fortune Capital Investment –re-upping. They were joined by a long list of new investors: Redmile Group, Arrowmark Partners, Hillhouse Capital Group, Mirae Asset Financial Group, Syno Capital, Haitong International Securities, Lucion Group, Sirona Capital, Alexandria Venture Investments and entities affiliated with Leerink Partners.

Current T-cell therapy approaches using chimeric antigen receptors (CARs) or engineered T-cell receptors (TCRs) have limitations.

CAR T cells generally don't work well on solid tumors, likely because they don't use the complete TCR complex of six subunits responsible for activating a cascade that leads to downstream activities including proliferation, activation, migration, cytokine release, persistence and cell killing.

Modified TCR T cells have the complete TCR, but they're limited by the human leukocyte antigen (HLA) system that presents antigens to T cells, which is often down-regulated on tumor cells. And there are more than a dozen HLA subtypes, so each construct will only work on a subset of patients.

To avoid those pitfalls, Cambridge, Mass.-based TCR2 developed its TRuC platform that conjugates a tumor antigen binding construct – such as a single-chain variable fragment, a single domain antibody or an antigen-binding fragment – to the TCR complex, allowing for complete activation of the T-cell functions through TCR while avoiding HLA matching.

Because the tumor antigen binding mechanism is just conjugated onto the TCR complex, it's possible to make a dual-targeting TRuC T cell by adding a second tumor antigen binding construct, which can reduce the likelihood of the tumor escaping detection through mutations in the first antigen.

TRuC T cells also produce lower levels of cytokines than CAR T-cell therapies, reducing the likelihood of a deadly cytokine release syndrome side effect that's plagued many CAR T-cell therapies. Using the entire TCR activates the part of the feedback loop that's responsible for modulating the cytokine response, which is absent in CAR T constructs.

The platform also allows for the addition of modulators that can help the T cells work in specific tumor microenvironments. For instance, TCR2 is working on a chimeric receptor that combines the PD-1 receptor with a CD28 stimulatory domain on the inside of the cell. The so-called PD-1 switch would turn the usual negative feedback from PD-L1 expressed on tumor cells into a positive signal.

Heading to the clinic

TCR2's lead program, TC-210, targets mesothelin, a glycosylphosphatidylinositol anchored surface protein that is overexpressed in a range of solid tumors but not on vital organs. Overexpression of mesothelin is associated with poor prognosis, giving it clinical rationale and leading Alfonso Quintás Cardama, TCR2's chief medical officer, to call mesothelin a "very attractive target," while noting that there are CAR programs targeting mesothelin in the clinic. (See BioWorld Today, April 21, 2015.)

Preclinical data has shown that TRuC T cells expressing anti-mesothelin single domain antibody can eliminate MSTO cells in a mouse model in 17 days, while CAR T cells were unable to eliminate the tumor in the same model system. Moreover, if the mice were re-challenged with tumor cells after eliminating the first tumor, the TRuC cells persisted, coming out of the spleen to stop the formation of a second tumor.

TCR2 plans to move TC-210 into a phase I trial in patients with ovarian, mesothelioma, cholangiocarcinoma (bile duct cancer), non-small-cell lung cancer (NSCLC) and pancreatic cancer. If an effective dose can be established, cohorts of the first four cancers will be tested in a phase II study.

For NSCLC, patients will be treated with TC-210 with and without a PD-1/PD-L1 inhibitor. If the company sees a synergistic effect with the combination, it'll provide rationale for moving the PD-1 switch into the clinic.

TCR2 has two other programs moving toward the clinic, a TRuC for solid tumors with an undisclosed target dubbed Program X and a dual-targeting TRuC simultaneously targeting both CD19 and CD22 for hematological malignancies.

Both programs are close to being ready for IND-enabling studies, but Menzel said the company wants to be smart about sequencing the programs based on opportunity, noting that the PD-1 switch program could leapfrog the two programs if there was rationale.

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