Novel IL-2 Agent Shows Promise in Advanced Solid Tumors

A phase I study showed activity with WTX-124, a novel interleukin-2 (IL-2) prodrug, in patients with locally advanced or metastatic solid cancers whose tumors progressed after checkpoint inhibition.

In this exclusive MedPage Today video, principal investigator Igor Puzanov, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, discusses findings from the study, which were presented at the recent American Society of Clinical Oncology (ASCO) meeting.

Following is a transcript of his remarks:

Through the study we presented here at ASCO is an exciting novel way to give interleukin-2. People know interleukin-2 as the cytokine, which really brought immunotherapy to the forefront many years ago. And we used to give it as a high dose interleukin-2, and that had to be given in an ICU [intensive care unit]-like setting with a lot of side effects, but also with cures for patients, especially with melanoma and kidney cancer.

So the next wave of drugs try to take this model and bring it to clinic, to make it a drug which is able to be given in a clinic without the ICU support. First couple of projects were unsuccessful, probably because we didn’t understand the biology enough, like the NKTR-214 [bempegaldesleukin], the Synthorx data. However, now the next wave of cytokines looks much more promising.

Interestingly, those cytokines have activity not just against IL-2 receptor beta and gamma, but also against alpha, which is almost counterintuitive because people say, well, if you have alpha, beta, and gamma, you will be supporting Tregs [regulatory T cells]. We are finding that is not the truth.

And our phase I trial, which we presented today with WTX-124 drug is a great example. So unlike NKTR-214 where there were no objective responses to the single agent, we actually have three objective responses to melanoma, squamous cell skin cancer, which is a complete response, as well as esophageal cancer. And we have several patients with almost partial responses, especially in very refractory patients with melanoma. These patients, all of them, had a dual inhibition of CTLA-4/PD-1. So this is a heavily pretreated population. Esophageal cancer, of course, is known not to be responsive to immunotherapy.

And what is different about the cytokine? So this is the whole molecule. So this is your whole molecule, IL-2. However, it has been modified in a way that it’s connected to the domain, which stabilizes it in the bloodstream, and it also has a little decoy, which prevents it to be inactive in the bloodstream until it gets to the tumor where the tumor-specific proteases will cleave that domain. And now the IL-2 will be active in situ in that tumor. So it’s like injecting interleukin into the tumor, however you don’t have to because it will get there by itself.

So the next step is for us to try to combine with checkpoint inhibitor pembrolizumab [Keytruda]. We are still working on perfecting the doses and the schedules because obviously that is the most important part on a phase I trial. However, knowing that we already have activity, we are expanding in tumor types such as melanoma, squamous cell skin cancer, head and neck cancer, and potentially others.

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