Using Vaccines to Bolster Immunotherapy Responses in Kidney Cancer

While vaccines have had difficulty in the treatment landscape of renal cell carcinoma (RCC), they are now being tested to possibly improve response rates with checkpoint inhibitors, says Tian Zhang, M.D.

Zhang notes that over the past 10 years, three viral vectors that test vaccines in kidney cancer — TG4010, MVA-5T4 and IMA901 — have not succeeded in clinical trials. “My question is, ‘Are vaccines a lost cause or are they a way forward?’ Certainly, there have been several lost causes that we've seen thus far, but as we get better at designing vaccines, hopefully this is a step forward in improving immunotherapy for kidney cancer,” says Zhang.

Could you provide an overview of vaccines in the treatment of RCC?

In an interview with CURE, Zhang, a medical instructor in the Department of Medicine, Duke University School of Medicine, discusses the challenges associated with vaccine development in kidney cancer and the hope that vaccines can still be the answer to improving the response rates with anti—PD-1/PD-L1 treatment in RCC.There is an excitement around checkpoint inhibitors in RCC. There is a question of whether there is a way to improve the response rate we see in checkpoint inhibitors with vaccines, due to its immunogenicity in RCC.

There have been three negative trials thus far of viral vectors that test vaccines in kidney cancer, transgene TG4010, MVA-5T4 and IMA901. These have, unfortunately, spanned the last decade in testing so it has been very hard to think about which tumor antigens are the optimal ones to target, which should we present to T cells to activate them, and which particular tumor antigens we should go after.

The transgene virus vector presents a specific tumor antigen and there is one from the IMA901 that presents about 10 different tumor antigens, but they are all prespecified and off-the-shelf. There is one from Argos that is a dendritic cell vaccine, which takes both dendritic cells as well as tumor RNA from patients directly and integrates those, so that, when infused into the patient, the dendritic cells will activate the T cells based on the patient’s repertoire of tumor antigens. That one showed pretty promising results in a phase 2 study and is currently undergoing a phase 3 in combination with Sutent (sunitinib) in the first-line setting.

I think the challenge in vaccine development is selecting those tumor antigens versus personalizing and targeting them to the patient. Secondly, there is an ever-rising bar of first-line treatment for metastatic RCC and so that first-line therapy and the comparison arm with certainty change in the ongoing trials and the trials we design in the future.

Finally, I think choosing the disease state is really important. Should we be introducing vaccines in the adjuvant setting versus first-line for metastatic disease and are there micrometastases in the adjuvant setting that we need to get to with vaccines, since these do take a longer time to illicit a response.

Are there any other trials ongoing that are looking at vaccines in combination with checkpoint inhibitors?

What is the potential impact of the combination dendritic cell vaccine plus Sutent trial?

My question is, “Are vaccines a lost cause or are they a way forward?” Certainly, there have been several lost causes that we've seen thus far, but as we get better at designing vaccines, hopefully this is a step forward in improving immunotherapy for kidney cancer.There are several ongoing studies—a phase 2 interim tumor dendritic cell vaccine, phase 1 studies in combination with checkpoint inhibitors. One of these phase 1 studies is in combination with Keytruda (pembrolizumab). I think these are early on in their clinical development but hopefully they represent a wave of combination therapies with checkpoint inhibitors that will change the field of kidney cancer treatment for the better.The promise is that the phase 3 trial will be positive, and it was compared in combination with Sutent as opposed to Sutent alone so if it is a positive trial I think it would change first-line treatment. I think we certainly saw improved progression-free and overall survival in the phase 2 trial, compared to historic controls. Although, as I alluded to earlier, in the changing landscape for first-line therapies, we need to think about combinations that have checkpoint inhibitors, as well. So, we want to figure out if vaccines improve checkpoint inhibitors, instead of just improving Sutent—which itself is a potential immunomodulatory agent, but may not have the activation mechanisms of checkpoint inhibitors.