Closely-held Triumvira Immunologics is developing a novel platform to engineer the immune system’s T cells to attack cancer using proprietary T Cell-Antigen Couplers (TACs).
“TACs were designed to use the natural activation and inhibitory pathways of T cells and have the potential to outperform identically-directed chimeric antigen receptor (CAR) T cells,” president and CEO, Dr. Tony Fiorino, says in an interview with BioTuesdays.com.
Dr. Fiorino explains that the company removes white blood cells from patients, uses genetic engineering to insert the TAC receptor into the T cells and direct them to recognize a protein found on the surface of certain cancer cells. “We expand these reprogrammed TAC-T cells so they can be administered back to the patient, where they are designed to find the cancer cells and kill them.”
CAR-T cells have shown impressive efficacy in various leukemias and lymphomas but are accompanied by significant, sometimes fatal toxicities, he contends. Industry leaders in CAR-T cell development include Novartis, Juno Therapeutics and Kite Pharma.
About 30% of CAR patients develop severe cytokine release syndrome, which requires admission to the intensive care unit, he points out. In addition, severe neurotoxicity is also common and probably related to increased cytokines, a condition he says can also be fatal.
TACs were designed for enhanced regulation and direct them to recognize a protein found on the surface of certain cancer cells.
“These toxicities may be driven by bypassing normal T cell activation pathways,” he suggests. “Our TACs engage the T cell receptor and have the potential to provide a better regulated activation of the T cell.”
Dr. Fiorino says McMaster University, where the TAC technology was developed, has filed patents around the technology, which Triumvira has licensed. “The novel design and function of TACs gives us clear freedom to operate,” he adds, “and we have additional patents in preparation.”
In a head-to-head experiment, comparing TAC-T cells and CAR-T cells, and targeting the HER2 cancer antigen, he says TAC-T cells demonstrated better potency, a dramatically improved toxicity profile and a better cytokine profile than CAR-T cells.
Immunodeficient mice treated with HER2-CAR T cells typically experienced a steep drop in body temperature, followed by death, regardless of the dose, and whether the mice were or were not implanted with human ovarian or breast cancer cells. A dose of 20 million TAC-T cells produced no overt toxicity and 100% of mice survived.
“We were very encouraged by these data because our hypothesis is that we can provide a safer alternative to a CAR,” he adds.
“We haven’t proven what caused the death of the mice but all indications point to an aberrant cytokine profile because we saw much higher concentrations of a number of cytokines in the CAR-T cell-treated mice and there was a massive infiltration of CAR- T cells in the lungs, liver and heart of the dead mice,” Dr. Fiorino says.
In solid tumor mice models, he says TAC-T cells had a stronger anti-tumor effect, with less cytokine secretion and markedly better toxicity than CAR-T cells. “These results also raise the possibility that TAC-T cells can be used against solid tumors that are poor CAR-T candidates,” he adds.
However, Triumvira’s lead candidates – CD19-scFv and BCMA-scFv – are targeting B-cell leukemias and lymphomas, and multiple myeloma, respectively. “We hope to be in the clinic within 18-to-24 months to establish proof-of-concept,” he predicts.
The company also is developing second-generation TAC products, with improved properties, and expanding into additional hematologic and sold tumor targets.
TACs were designed to use the natural activation and inhibitory pathways of T cells and have the potential to outperform identically-directed chimeric antigen receptor (CAR) T cells.
CD19 is a cell surface protein on B cells. CD19-positive B cell malignancies include acute and chronic lymphocytic leukemias and non-Hodgkin’s lymphoma. Combined they represent approximately 50,000 cases a year in the U.S. and similar numbers in the EU.
Several CD19 CAR-T programs are in pivotal studies, including those in development by Novartis, Juno and Kite. The first CAR-T therapies could be approved in the U.S. in 2017 and 2018.
“CAR-T efficacy and cytokine release syndrome rates from ongoing pivotal studies will allow us to benchmark our TAC-T cells against CAR-T cells in a pilot study with as few as 20-to-25 subjects, ” Dr. Fiorino points out. “Our trial is expected to run in Canada owing to the expected commercial availability of CARs in the U.S.,” he adds.
The company is targeting yearend pre-clinical trial application and pre-IND meetings in Canada and the U.S. to discuss the program going forward.
Several CD19 CAR-T programs are currently in pivotal studies and could be approved in the U.S. in 2017 and 2018.
BCMA is a cell surface protein found only on multiple myeloma cells. Multiple myeloma is a malignancy of plasma cells, which are derived from B cells and secrete antibodies. There are about 50,000 new cases a year the U.S. and EU combined and the disease represents a significant unmet medical need. Patients commonly endure multiple lines of therapy, eventually becoming refractory to treatment.
Dr. Fiorino says there are fewer BCMA CAR-T programs in clinical development than CD19. Investigators from the NIH in December reported results at ASH from a first-in-human trial of a CD28 CAR-T program. At the highest dose tested by the NIH (900,000 cells per kilogram), severe cytokine releasing syndrome was observed in two of two subjects.
Triumvira’s BCMA TAC-T cells kill myeloma cells in culture and the company is moving the program into animal models, he points out, adding that the BCMA program is about six months the CD19 program. “We’re probably going to need outstanding data for this program to move forward.”
Dr. Fiorino says the company should have its data collection completed by the end of 2016. “The rate limiting step for us to get into the clinic is manufacturing.”
While the company is conducting scale-up of its manufacturing process in its lab, it plans to initiate a technology transfer at the beginning of 2017 to a clinical manufacturing facility.
Triumvira plans to seek a series A financing of $30-million to complete its clinical proof-of-concept studies for CD19 and BCMA and discussions with interested VCs are underway.
“We believe the platform and IP creates strategic value for Triumvira and for potential partners, and is complementary to many other engineered T cell approaches,” he contends.
