Novel Immunotherapy Approaches for Urothelial Cancer - Episode 4

Promise of DNA Vaccines in Bladder Cancer


Jonathan Rosenberg, MD: One approach that we’re using is utilizing vaccine therapies to target cancer. In bladder cancer, one approach that’s being tested is a combination of multiple different antigens in a vaccine preparation called INO-5401. This is an injectable DNA vaccine that targets WT1, HTERT, and PSMA—all of which are tumor antigens that are overexpressed in bladder cancer. It’s also combined with an immune-stimulatory molecule, IL-12, to allow for the immune system to recognize these antigens and hopefully attack the cancer. It’s being combined with an immune checkpoint blockade. In other studies, it’s been shown that these DNA vaccines are generally quite safe, without a lot of toxicity. Therefore, they show a lot of promise in combination with the immune checkpoint blockade, particularly in bladder cancer where patients often have multiple comorbidities that prevent them from being treated with highly toxic therapies.

This vaccine is delivered via electroporation, where there is actually a proprietary system that’s used, almost like a gun. It’s applied to the patient’s skin, and it injects the vaccine directly into cells with an electric current. This causes the DNA to be taken up into cells. It is presented to the immune system, along with the immune-stimulatory molecule, which then acts on the tumor microenvironment to recruit immune cells. This educates the immune system, hopefully sending these cells out to other places in the body, to find these antigens and attack cancer cells.

This sort-of approach has shown early evidence of efficacy in cervical cancers and cervical intraepithelial neoplasia, which is a virally mediated disease that uses different targets. But the concept is that the immune system will recognize and actually attack these precancerous or noninvasive malignant lesions in cervical cancer. This is being tested in a randomized phase III trial right now. In bladder cancer, this vaccine is going to be combined with atezolizumab, one of the PD-L1 targeted immune checkpoint drugs, and we hope to see some data on this combination in coming years. The idea would be that the immune system is now poised to respond to the cancer and that the addition of a vaccine therapy would increase the likelihood of tumor regression in these patients. This is really being tested, first, in patients who have progressed following immunotherapy with a checkpoint inhibitor. There is the idea that we may see immune responses and clinical responses that, in fact, are really related to the vaccine rather than to the continued use of an immune checkpoint agent.

This trial is targeted toward patients who have metastatic urothelial cancer who have previously progressed on an immune checkpoint agent. These patients have to be fit enough to go on a clinical trial. If they have progressive cancer on an immune checkpoint drug, the likelihood of them having an additional response to continued immune checkpoint therapy is very low. The hope is that with the addition of the DNA vaccine, this will induce an immune response that will be durable. Consequently, patients would derive a substantial benefit from that. Then it would move testing to earlier stages of bladder cancer, with larger clinical trials.

Transcript Edited for Clarity