The Potential of ALLO-316 in CD70-Expressing Advanced RCC

Samer A. Srour, MD

Results from the phase 2 TRAVERSE trial (NCT04696731) revealed the encouraging anti-tumor activity with ALLO-316, an allogeneic chimeric antigen receptor (CAR) T-cell product, in patients with advanced or metastatic renal cell carcinoma (RCC), including those with CD70 expression.¹

The study continues to accrue patients and will soon enter its expansion phase, according to Samer A. Srour, MD.

“These findings, in the context of the phase 1 clinical trial at low dose levels, are very encouraging. We continue to accrue, and we are planning to expand further, hopefully, towards the end of this year,” said Srour, assistant professor, Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, in an interview with Targeted Oncology™.

A total of 18 patients were included in the efficacy analysis, 10 of whom were positive of CD70 expression. The overall response rate in the overall population was 17%, and in the CD70-positive population, it was 30%. The disease control rate (DCR) in the overall population was 89%. In the CD70-positive population, the DCR was 100%.

Nineteen patients from the study were evaluable for safety. Among them, there was only 1 dose-limiting toxicity (grade 3 autoimmune hepatitis at dose level 2). All cases of cytokine release syndrome (CRS) were low-grade with the exception of 1 patient who had grade 3 CRS. The most common any-grade adverse events included CRS (58%), infusion-related reaction (5%), and neurotoxicity (68%).

In an interview with Targeted Oncology™, Srour, discussed the TRAVERSE study results in detail and explained the potential role ALLO-316 can take on in the space.

TARGETED ONCOLOGY: Can you explain the need for novel agents to treat clear cell RCC?

Srour: Patients with kidney cancer who have failed first-line therapies, particularly checkpoint inhibitors and tyrosine kinase inhibitors, usually have poor outcomes. This is because there are no good, alternative treatments. Most of the other treatments available are much more of a palliative approach. You use them for a few months, and then most patients end up unfortunately dying from their disease. To that extent, we are in need of novel agents, like our cell therapy approach, for these patients who otherwise will die from their disease.

What can you say about ALLO-316 and what sets it apart from other agents for clear cell RCC?

As I mentioned, these patients with advanced relapsed/refractory clear cell renal cell carcinoma will fail the standard checkpoint inhibitors or TKIs. They have an overall poor prognosis. Among other treatment options, the cell therapy options sounds like one of these promising approaches to treat kidney cancer for different reasons.

First, we have a proof-of-concept from our experience in the hematologic malignancies that chimeric antigen receptor, when they are engineered and redirected to a specific antigen on the cancer cell, they can induce durable remissions in, on average, 30%-40% of the patients over 3 or 4 years. We carry our heavy experience from the hematologic malignancies into the solid tumor space. ALLO-216 is 1 of these novel attempts to counteract all the challenges in solid tumors, and particularly kidney cancer in this study.

ALLO-316 targets CD70, which is one of the tumor antigens highly expressed in kidney cancer. CD70 has very low expression in normal tissues, or no expression on normal physiologic tissues. It is known from literature, preclinical studies, and early clinical studies that CD70, when expressed on tumor cells, can make the cancer aggressive, and it can suppress tumor microenvironment.

With ALLO-316, we are marking out CD52 to allow us to use the other 6 or 7 which are anti-CD2 antibodies, which contain our lymphodepletion and help us to expand and persist over time. There are additional edits, like masking the CD70 expression. It also knocks out the direct gene which prevents graft-versus-host disease. In addition to that, this novel agent has a safety switch. If the patient had excessive, unexpected toxicity, we could use a CD20 antibody to kill it.

Can you explain the key goals of this study?

Like any phase 1 study, our primary objective was to assess safety and tolerability of the product because this is the first time in humans in a clinical trial. The secondary objectives were to assess preliminary anti-tumor activity and the presence of ALLO-316 antibodies.

So far, we enrolled 20 patients, and 19 of them have been infused with ALLO-316.

What is significant about the results presented at AACR 2023?

If you look at the safety data, we did not see any unexpected safety signals. Most of the adverse events we saw were similar to the ones we see with autologous CAR T-cell products.

For efficacy, although this is secondary objective, we were encouraged to see that at low dose levels, there were very promising and encouraging responses if you take patients who have CD70-positive expression. Again, this ALLO-310 targets CD70. We have a 100% disease control rate, and we have a 30% objective response rate, which means patients responded with significant shrinkage of their tumors. These findings, in the context of the phase 1 clinical trial at low dose levels, are very encouraging. We continue to accrue, and we are planning to expand further, hopefully, towards the end of this year.

Can you discuss the exploration of CAR T cells in solid tumors? Why is this important?

We have been doing this for maybe 2 decades, but the success of it, , as we've seen with [ALLO-316], that is something new. I would say over the last 3 to 5 years, there has been a renewed interest in exploring more CAR T-cell therapies in solid tumors. First because we have been successful in hematologic malignancies. Then, we got the FDA approval, a historic approval for a CAR T-cell product in lymphoma and leukemia. That renewed our interest that we can do something, even in solid tumors.

We have several studies, maybe hundreds of studies, across not just United States, but abroad. We are trying different modalities to improve the outcomes in prostate cancer, thyroid cancer, ovarian cancer, breast cancer, and lung cancer. You name it.

I run several of these studies, which have basket studies as well. We look at targets and then we identify the percentage of that tumor antigen we treat them. I think overall, we are starting to overcome many of the challenges in several tumor subtypes. We are encouraged with results like ALLO-316 and some others. We are getting into that new era where we will, hopefully soon in the coming few years, be able to establish some sort of new standards.

_REFERENCES:

_{Allogene Therapeutics presents interim phase 1 data on ALLO-316 in renal cell carcinoma at the American Association of Cancer Research (AACR) Annual Meeting. News release. April 17, 2023. Accessed May 8, 2023. https://bit.ly/44IZAns}