The main challenge in developing targeted therapies for cancer is finding the right target. Drug hunters are looking for a protein that is abundant on cancer cells but absent on healthy cells, so that the effect of the therapy is concentrated on the tumors. But sometimes the effect still spreads to healthy tissue, causing dangerous complications.
Currently available cancer immunotherapies are designed to address specific targets, but these antibody drugs and engineered T-cell therapies have not yet solved the targeting problem, said Stefan Scherer, CEO of biotech startup 3T Biosciences. These therapies target tumor cell surface targets, and easy targets have already been discovered. To identify new targets that are unique to the tumor, Scherer argues, the search must go inside those cells.
“What we’re discovering is a whole new universe of targets,” said Scherer, a pharmaceutical industry veteran whose experience includes executive roles at GSK, Cellectis and Novartis. “With these targets, we believe we can be very tumor-specific and address tumors in a way that is different from what has been considered before.”
South San Francisco-based 3T Biosciences has been quietly developing its technology over the past few years. On Thursday, it unveiled its approach to improving cancer immunotherapy along with the support of $40 million in Series A funding. The investment round was led by Westlake Village BioPartners with participation from Lightspeed Venture Partners.
Currently available cancer immunotherapies may have drawbacks, but they still have value in 3T research. The drug discovery process in biotechnology begins with tumor samples from patients who have responded to immunotherapy. These samples come from academic centers and institutions that have collected tissue as part of clinical research. In these patients, the immune system has identified or discovered something that 3T can use, Scherer explained. What the company is looking for is a partner between a T-cell receptor (TCR) and the molecule that binds it.
3T technology can be used to develop three types of drugs: TCR cell therapies, peptide vaccines, and bispecific antibodies. Scherer said the company will focus on developing bispecific antibodies, molecules that have one arm that binds to a tumor target and the other binds to a T-cell target. Binding to both simultaneously guides the T cell to the tumor to destroy the cancer cell.
FDA-approved bispecific cancer antibodies treat only blood malignancies. Solid tumors remain difficult for targeted therapies because of their heterogeneity, the variety of cells within a tumor that makes it difficult to identify the right targets. Other biotech startups as well as large pharmaceutical companies pursue bispecific approaches to solid tumors. But 3T aims to show that its technology can stand apart from the field. More than identifying new tumor-specific targets, 3T claims its technology also enables biotechnology to make therapy safer. Using protein engineering techniques, Scherer said the company can remove any binding of the molecule to an unwanted target, such as one found in the heart or lungs.
3T aims to avoid some of the pitfalls encountered in previous TCR research efforts. While Adaptimmune advances with TCR used in their experimental cell therapies, this progress has followed fatal setbacks. One of the early Adaptimmune cell therapies resulted in the death of patients in a clinical trial. This therapy uses the patient’s own T cells engineered with a TCR that binds to a cancer target. However, the receptor was later found also to target a peptide in a muscle protein expressed in cardiac muscle cells. This cross-reactivity resulted in fatal cardiac complications in two patients.
Scherer said 3T’s technology not only screens for TCRs that are specific to cancer cells, but also identifies targets that don’t pose cross-reactivity problems. The tumor samples collected by 3T provide additional help in improving the side effect profile of its drugs. Analysis of these samples revealed what triggered a complication such as an excessive immune response called a cytokine storm, a potentially fatal complication of the CAR T class of immunotherapies. With this activation information, the technology can predict what triggers a side effect and what doesn’t. The company can then use protein engineering to alter the molecule, reducing the risk of side effects.
The technologies underlying the 3T approach are licensed from Stanford University, where they were originally developed in the laboratory of C. Christopher Garcia, a professor of structural biology who has specific expertise in TCR. The company spun off from Stanford in 2017 – the same year the first CAR T-therapies designed to target the cancer protein CD19 won FDA approval.
3T was initially supported by seed funding from the Parker Cancer Immunotherapy Institute, among others.
Over the past five years, 3T has further developed its technology and automated it, Scherer said. The young company has built its own library of tens of thousands of isolated TCRs and hundreds of thousands of connectors, all filtered through the technology’s machine learning algorithms. The research has discovered more than a dozen new targets, and 3T is designing drugs to hit them. With the new funding, Scherer said the company aims to move into clinical testing in 2023 or 2024.
While cancer is the main focus of 3T, the ability to identify TCRs can also be applied to drug discovery for autoimmune diseases. Scherer said the study of autoimmune diseases has drawn interest mainly from academic collaborators. But this application of the technology also offers potential for partnerships with companies looking to work with 3T outside of oncology, he said.