Wistar scientists have developed a new type of bispecific T cell engagement, or BTE, that is effective against ovarian cancer in preclinical studies. It’s a major development for this type of immunotherapy, which has been used successfully against blood cancers but has so far been less effective in solid tumors.
The researchers developed a new “knob-in-hole” platform to deliver BTE, by which they construct an antibody “knob” that is forced to fit into an antibody “hole,” resulting in two puzzle pieces that fit together perfectly.
They showed that BTEs could be delivered with DNA-based technology, a powerful approach that could significantly reduce production costs and the treatment burden for patients. They also developed a way to deliver two different antigen-targeting BTEs in a single dose, a key strategy for overcoming therapeutic resistance.
“I think it’s a major advance for the field of bispecific antibodies,” said Pratik S. Bhojnagarwala, Ph.D., a postdoctoral fellow in the laboratory of David B. Weiner, Ph.D., at the Wistar Institute’s Center for Vaccines and Immunotherapy and first author of the study. “It is also important for ovarian cancer, where there is a real need for new treatment options, but there are probably wider applications for other solid tumors as well.”
Bispecific T cell adjuvants are a powerful immunotherapy that has seen significant growth in clinical use over the past 10 years. They help the immune system fight cancer by physically grabbing cancer cells and disease-fighting T cells and bringing them together, which redirects T cell killing against cancer cells.
Existing BTEs have been ineffective against solid tumors such as ovarian cancer, in part because of their short half-life, which causes them to be rapidly cleared from the body. Solid tumors are also less uniform than blood cancer cells, making them better able to evade BTEs, which work by targeting a single antigen on the surface of the cancer cell. New technology solves both problems.
The first key innovation is the use of a DNA-based delivery platform to make the patient’s own muscle tissue act as a “factory” that produces BTEs directly inside the body. The knob-in-the-hole design adapted for DNA delivery by the researchers further improves the half-life of BTEs, making them last longer. This approach is more affordable, easier to make, doesn’t require refrigerated storage, and lasts longer with fewer doses, Bhojnagarwala explained.
The researchers also showed that they could use the platform to deliver two different BTEs simultaneously, an approach that is more effective at targeting the different antigens found in solid tumors.
Showing that we can deliver these truly complex molecules in vivo in mouse models was a very exciting achievement that demonstrates its potential as a next-generation tool to improve patient outcomes. The cost of treatment could become less expensive and we could also need fewer doses because the body’s muscle cells continue to produce it, rather than having to come back for multiple doses.”
Pratik S. Bhojnagarwala, First Author
In a preclinical model, the researchers showed that the new BTE lasted longer in the body and was more effective at slowing tumor growth. They also conducted a lab study that showed it worked in human cells from ovarian cancer patients. Another experiment showed that it could be combined with an immune checkpoint blockade, an immunotherapy commonly used in solid tumors, to make the treatment more effective.
Next, the researchers plan to test the treatment in more advanced human cell models, taking it one step closer to human trials. They also hope to study it against other cancer targets.
