Immunotherapy has been the holy grail in the fight against cancer for the last decade. For good reason, we’ve been inspired by the power of redirecting the human body’s immune system to hunt down and kill cancer cells, and we’ve been emboldened by the successes of checkpoint inhibitors like anti-CTLA4, anti-PD(L)-1 and anti-LAG3. When immunotherapy works, it works spectacularly and fundamentally changes the game in cancer treatment. But that progress comes with some enormous limitations. Far too often, patients’ tumors do not respond to immunotherapy, or they respond initially, but the benefits quickly wane.

CBL-B inhibition holds the potential to address several key mechanisms important in immuno-modulation, and that’s what makes us so excited about the work we and others are currently doing targeting CBL-B. CBL-B is an intracellular E3 ligase that serves as a master regulator of immune cell function. By inhibiting CBL-B, it is easier for effector immune cells to be more robustly activated and to be less susceptible to being suppressed in the tumor microenvironment. We believe those attributes are key to a more targeted, durable immune response that will usher in the next wave of immuno-oncology innovation.

Stoking the Flames of Existing Immunotherapies

In fact, we’ve just presented two new pieces of research at the annual Society of Immunotherapy of Cancer 37th Annual Meeting (SITC), which help to illustrate that progress. Our two posters highlighted how HotSpot’s CBL-B inhibitors drove anti-tumor immunity in vitro and in vivo. Importantly, the research shows how, in the mixed lymphocyte reaction (MLR) assay, which is a strong predictive correlate of the clinical activity of I-O therapies, the HotSpot CBL-B inhibitor demonstrated robust effects on cytokine release and T cell proliferation as a monotherapy. Importantly, HotSpot’s molecules outperformed other late-stage and approved mechanisms, including anti-LAG3 and anti-TIGIT. 

The research also illustrates how a HotSpot CBL-B inhibitor demonstrated immune-mediated tumor growth inhibition in multiple syngeneic mouse models, once again as a monotherapy. Gene expression profiling additionally provided support for how the CBL-B mechanism stimulates the immune system to proliferate and kill within the tumor microenvironment. These effects were notable with CBL-B inhibition alone and further enhanced when combined with a PD-1 inhibitor.

Put simply, our CBL-B inhibitors have the potential to spark a more aggressive immune response as an orally-dosed monotherapy, which could be a key development for tumors that are not responsive to more traditional PD-1 inhibitors alone.

An Allosteric Approach to Immunotherapy

We believe the key to unlocking that response is natural hotspots. Our allosteric approach to drug development targets unexploited pockets on proteins that control their function – their natural hotspots. By taking control of the hotspot on CBL-B, we’ve demonstrated the potential to selectively activate and/or propagate a targeted immune response inside a tumor that is trying to shut it down. We believe that’s a level of precision and control that is simply not possible in the world of traditional active site target drug development, and it represents a very exciting new frontier for cancer treatment.

In fact, by using our Smart Allostery™ platform, which uses computer algorithms to identify functional pockets on proteins, we have been able to identify over 1,500 natural hotspot-driven proteins. Once identified, the associated molecular on/off switches can be pirated by small molecule drugs, opening up huge opportunities to take control of the cell to drive a desired effect.

Most importantly, though, the data presented at SITC suggest that our CBL-B inhibitors could drive a biological effect that we hope will deliver clinical benefit where there is substantial need – in patients where standard of care with anti-PD-1 therapy doesn’t work very well, and in patients where anti-PD-1 therapies work somewhat but deeper and more durable anti-tumor effects are needed.

We believe the biological attributes of CBL-B inhibitors and the convenience of an oral medicine for patients represent a real turning point for immunotherapy, one that will help further deliver the promise of immunotherapy to even more patients.