TC BioPharm CEO Bryan Kobel/Courtesy of TC BioPharm
TC BioPharm (TCB) is developing a new approach to chimeric antibody receptor (CAR) T-cell therapies with the potential to eliminate off-target effects, meaningfully enhance quality of life and, possibly, expand the number of patients who can benefit from this type of immunotherapy.
The key is to use a co-stimulatory approach – an on-off switch – to prevent the outsized killing of healthy cells and the occurrence of cytokine storms that often cause patients to enter intensive care units (ICUs). To do this, TCB harnesses the innate mechanism of action of Gamma Delta T-cells and its natural antigen, isopentenyl pyrophosphate (IPP).
“Our co-stimulatory approach is a natural iteration in the advancement of CAR therapies,” Bryan Kobel, CEO of TCB, told BioSpace. As he explained, “IPP is expressed by all sick and diseased cells, so all solid tumors emit this antigen. If that CAR attaches to a healthy cell, but there is no IPP, the Gamma Delta T-cell does not attach and the CAR breaks away. When it finds a tumor or unhealthy cell and both the CAR and the Gamma Delta T-cell attach and complete the biological circuit, the activation signal is sent and the CAR-T gamma kills the cell." Therefore, there is expected to be no, or minimal, toxicity.
“Usually, the issue is getting the Gamma Delta T-cell out of the vasculature and into the tissue,” Kobel continued. “Now there’s evidence of certain variants of Gamma Delta being present in the tissue around tumors. They’re also in the lamina propria of the gut, to combat cancers and viral infections. Therefore, we know they leave the vasculature and hone in on the tissue and find cancer and other diseased cells there.”
With standard CAR T-cell therapy, one of the biggest issues has been on-site, off-tumor toxicity. That sometimes happens because some of the CAR binders exist on healthy cells, limiting dosing size and making it complicated for these CARs to permeate out of the blood into solid tumors in tissue. As Kobel elaborated, the targets for the frequently-used CD-33, CD-19 and C-11 CAR binders “exist on disease cells, tumor cells and very healthy cells, so when you dose a patient, you have a therapeutic that kills healthy cells as well as those with disease and can result in cytokine storm syndrome among other issues. There’s a better than 50% chance that the patient will need an ICU bed,” which drives up the cost of care.
TCB has two approaches, each of which appears efficacious and economical compared to current therapeutics.
One combines unmodified Gamma Delta T-cells with CAR therapy, which the company is developing for solid and hematological cancers. Several programs are in preclinical development in-house and with partners. “If you have a non-toxic or low toxicity treatment with a high degree of efficient killing, you should be able to treat a much larger patient population,” Kobel theorized.
The other is to expand unmodified Gamma Delta cells and reinfuse them into a patient’s body. “They will do what they’re already doing, just in much greater numbers. That unmodified dynamic could serve a large swath of the patient population. Importantly, given the potentially low cost of the therapeutic, that includes the underserved and economically disadvantaged,” Kobel said.
A Phase IIb/III clinical trial using this approach is underway in the U.K., using TCB's lead product, OmnImmune, to treat acute myeloid leukemia (AML). This is an unmodified allogeneic Gamma Delta T-cell therapy. It was granted Orphan Drug status by the U.S. Food and Drug Administration based on TCB's Phase Ib/II data. This particular trial assesses feasibility as “a bridge to bone marrow transplants, hopefully stabilizing the disease,” Kobel said, so a transplant could be performed.
Data from studies of fourth-line AML patients – relapsed, refractory patients with about four to six weeks to live – was positive. “We treated them with a medium dose – about 600-700 million cells. By day 28, after one dose, the average blast cell count went from 38% disease to 6% disease. We had two complete responses and one patient who lived more than two years after our treatment. The complete responders' blast cell counts went from 60% to below 5%, and (they) were able to return to other treatments,” Kobel said. “We imagine that when we go into healthier patients we will see a similar, if not better, response.”
The approach for all of TCB's therapies uses donor blood from healthy people with activated Gamma Delta T-cells. In contrast, other CAR T-cell immunotherapies typically draw blood from patients, isolate and expand the Alpha Beta T-cells and then return them to patients. That is difficult when patients are very sick and have suppressed immune systems.
As TCB developed this platform, it also considered efficient, economical manufacturing processes. Its manufacturing facility was completed in 2015 and those methods have been refined continually. For example, Kobel said, “We just took more than 200 steps out of the process during the COVID-19 pandemic and also advanced OmnImmune to being a frozen-thawed product. This means we can now ship and store our cell therapy at facilities around the world, making it truly off-the-shelf.”
TCB has an advantage in that one of its co-founders, COO Angela Scott, manufactured the first stem cell stroke treatment for a neuron and, at PPL Therapeutics, was part of the Roslin Institute team that created Dolly the sheep (the first mammal cloned from adult somatic stem cells). Kobel called her “our secret weapon to quickly optimizing our manufacturing process.”
The company’s commitment to efficiency also extends to dose delivery, with a deep-frozen product that it stores at a CryoPort facility in Texas. “When a patient needs our product, it is dropped into water for about 5-10 minutes to thaw it, and then infused into the patient. That makes this more off-the-shelf than most cell therapies today.”
The goal is not only to make a safer, more effective CAR T-cell therapy but to make it in a way that puts it within reach of patients who today lack access to such advanced therapy.
