Hammers Recommends Revisiting Vaccines in Renal Cell Carcinoma

Hans J. Hammers, MD, PhD

The list of immunotherapeutic agents that show positive results in renal cell carcinoma (RCC) continues to grow, with researchers exploring different combinations, including the addition of vaccines, in this arena. In particular, findings from a phase I study of alpha-1, 3 galactosyltransferase-expressing allogeneic RCC immunotherapy are encouraging, according to Hans J. Hammers, MD, PhD, associate professor, University of Texas Southwestern Medical Center, Dallas.

In the small study, patients with metastatic RCC were treated with HyperAcute Renal (HAR) immunotherapy. This vaccine consists of 2 allogeneic renal cancer cell lines, which have been genetically modified to express alpha-1,3-galactosyltransferase, a carbohydrate that humans have an inherent pre-existing immunity. By targeting alpha-1,3-galactosyltransferase, the immune system can begin to identify antigens expressed by the patient’s own tumor cells, says Hammers. “The idea is that cell lines that have been modified in this particular manner can jump-start an immune response.”

In this phase I dose escalation study, patients received a weekly injection of HAR (150 x 106 cells/300 x 106 cells intradermally) for 4 weeks, followed by biweekly injections for the next 10 weeks. Results showed tolerability and suggested that RCC is an appropriate tumor type regarding combination immunotherapy including HAR.

In an interview withTargeted Oncology,Hammers discussed the role of vaccines, potential next steps, and the future of immunotherapy in RCC.

TARGETED ONCOLOGY:Could you provide an overview of the phase I study on alpha-1,3- galactosyltransferase?

Hammers:

The treatment is an allogeneic renal cell carcinoma vaccine, meaning these are cell lines derived from different patients than the patient being treated. They have been genetically altered to express a certain sugar molecule, alpha-1,3-galac- tosyltransferase, that we see, for example, in pigs. In fact, most of the antibodies that we have circulating in our blood, actually are formed against alpha-1,3-galactosyltransferase. So, if you either transplant an organ from a pig or inject cancer cells that have been spiked with alpha-1,3-galac- tosyltransferase, they would be rapidly destroyed, leading to active inflammation.

These were 2 different cell lines, and the patient received subcutaneous injections in essentially 2 different doses. Drug development for vaccines is much less complicated than it is for targeted agents. The trial was designed in a way that patients initially received injections once a week for 1 month and then every 2 weeks thereafter. It was also designed in a way that patients were not allowed to have any concurrent therapy for the first 2 months, but then could combine it with any standard-of-care therapy thereafter, such as tyrosine, but also immune checkpoint inhibitors as they became available.

What we presented at the GU [Genitourinary Cancers] Symposium are safety data on the 15 patients that we have more details on. And overall, there were no big surprises—it is very well tolerated, with mostly local reactions, and in the end, we have a dose that can move forward into phase II studies.

TARGETED ONCOLOGY:Are there any next steps for future clinical trials?

Hammers:

We know it’s safe to do, but we still have to wait for some data—a subset of patients was actually treated with nivolumab (Opdivo) after 2 months. We stand to see what kind of impact it has—if there is some sort of clinical activity that might be enhanced. But I do think it deserves at least testing in combination with nivolumab, but to some degree it’s also a commercial decision by the company, if there is enough promising data. The goal of this phase I trial is achieved — we have a safe dose. Now there are several other aspects that play into this.

TARGETED ONCOLOGY:What do you want community oncologists to take away from this study?

Hammers:

I think the main message is that maybe it is time to revisit vaccines. We’ve spent a lot of time on the ridiculed recent trials that have been negative. There was a very large phase III trial that was negative, but vaccines have not really been tested in the context of immune checkpoint inhibition, and to some degree, that’s a natural marriage. We do know that vaccines will face challenges, in particular with what we’ve learned about immune checkpoints. So, combining vaccines with immune checkpoint makes a lot of sense.

There will be different approaches—allogeneic vaccines can be taken off the shelf very easily, but may not be as individualized as if you were to focus on analyzing a patient’s tumor and created tailor-made vaccines for the individual patients. But, that’s a more advanced approach. I think we will see several of these concepts tested in the clinic, I don’t know if they are going to work, but I do think that vaccines need to be visited and that’s what we will see.

TARGETED ONCOLOGY:What is the current role of immunotherapy in RCC, and where do you see it in the future?

Hammers:

I think it is a really exciting time in kidney cancer. We have had an immune checkpoint inhibitor— nivolumab—approved since November 2015; nobody is unfamiliar with these agents anymore. The question really is, where do we go from here? It is an agent, if used alone, that has moderate activity. Response rates are around 20%; these can be durable responses but they are simply not enough if you want to treat patients effectively with immunotherapy. I think there are several different approaches—one is to combine it with other agents such as targeted agents.

One marriage that I think is quite natural is combining VEGF [vascular endothelial growth factor] inhibitors with nivolumab. What we’ve learned is that it is probably better to use selective agents such as axitinib (Inlyta), rather than sunitinib (Sutent) or pazopanib (Votrient), and those combinations are moving forward in phase III trials. We have some data emerging from smaller phase II trials with very encouraging activity and very high response rates, as presented at ESMO [European Society for Medical Oncology] in the combination of axitinib and pembrolizumab (Keytruda).

The questions are going to be how durable are those responses, what’s the quality of response, and do we really see true synergy in an immunological perspective? Another combination, that is a competitor to some degree, is the combination of programmed cell death protein-1 inhibitors and cytotoxic T-lymphocyte-associated protein 4 inhibitors. There is a very large phase III trial that we are looking forward to seeing data on as early as this year, which compared the combination of nivolumab and ipilimumab (Yervoy) versus sunitinib. This could also be a changing standard of care. We know with this particular combination, the response rates are high—we expect to see response rates around 40%— and they tend to be quite durable with a median duration of almost 2 years.

One data set that I am very curious about is the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin). I think this might give us the first hint of synergy between VEGF inhibitors and PD-L1 [programmed death-ligand 1] inhibitors—and how durable might those responses be. I think it is a very important trial, and we will see if that is going to guide us in a certain direction.

Reference:

Hammers HJ, Drake CG, Zakharia Y, et al. A phase 1 study of alpha-1,3- galactosyltransferase-expressing allogeneic renal cell carcinoma immunotherapy in patients with metastatic renal cell cancer. J Clin Oncol. 2017;35(suppl 6S; abstr 528).