Dr Judy Wang on the Potential of CLN-619 for the Treatment of Solid Tumors

Judy Wang, MD, medical oncologist and clinical trials investigator at Sarah Cannon Research Institute at Florida Cancer Specialists and Research Institute, discussed the mechanism of action and rationale for studying CLN-619, an anti-MICA/B antibody, with and without pembrolizumab in patients with solid tumors.

The findings were presented at the 2023 American Society of Clinical Oncology Annual Meeting.

Transcript

Can you discuss the mechanism of action of CLN-619, particularly the activation of a receptor on both the innate and adaptive immune system? Why is this important?

The study CLN-619, this was a phase 1, fully human monoclonal antibody to what we call stress-induced ligands, MICA and MICB. In normal settings, MICA and MICB, these are receptors that are present on the surface of stressed cells, and that could be not only infections, but also cancerous cells. And they act as a means of addressing cells that need to be purposefully removed, proteolytically destroyed through our innate cellular immunity.

However, tumor cells have a way of eliminating presentation of MICA and MICB by proteolytically cleaving it with proteozymes that are present within the tumor microenvironment. And when MICA and MICB are not present on the surface of tumor cells, they're not able to engage an activating receptor called NKG2D, which is a means of activating not only NK, or natural killer cells, but cytotoxic T cells that are a big part of our cellular immunity. And when they're not able to bind, it acts as a means of immune evasion. And so therefore, these tumors are allowed to kind of propagate and progress in the face of an active immune system.

So, what CLN-619 strives to do is to restore that MICA and MICB expression by not only kind of anchoring it and binding it to the surface of these tumor cells, but helping to engage receptor binding to NKG2D, so that we can have both cellular innate and adaptive immune killing through our NK and T cells. As you can imagine, both of these prospects of of immune activation—both innate and adaptive immunity—are important in the sense that they are complementary aspects of our immune system, but particularly adaptive immune activation can lead to, for example, memory cells that may be able to provide prolonged and lasting immunity, following an active treatment with these agents.

We are seeing more therapies that work across tumor types being studied with and without pembrolizumab. Can you discuss the rationale for this approach?

It's important to be able to offer some of these therapies both in monotherapy and in combination, particularly for the monotherapy where we may be looking at disease groups that have already progressed after initial conventional checkpoint inhibition. There's an unmet need for for treatment options for these patients, and being able to reengage and activate the immune system through a different avenue, not through conventional checkpoint inhibition, is going to be attractive for those disease groups. So we're excited that we're starting to see some activity in the monotherapy-treated patients. Likewise, for the combination with pembrolizumab or other checkpoint inhibitors that may be beneficial, particularly for disease groups where we don't conventionally see good responses with monotherapy checkpoint inhibition, that perhaps having a combination where we see some synergy that we may be able to really engage the immune system and do cellular activation through for disease groups that we otherwise wouldn't see a response to monotherapy.