HB-200 Vaccines Show Promised in HPV16+ Cancers

Marshall Posner, MD

Adding pembrolizumab (Keytruda) to the HB-200 vaccines may help to improve efficacy in patients with human papillomavirus 16- positive (HPV16+) cancers, according to data from a phase 1 study.

HPV16+ cancers are caused by the expression of E7 and E6 oncoproteins, which is a source of immunogenic neoantigens. A tumor-specific T-cell response is induced by replicating arenavirus vectors HB-201 and HB-202.

The study (NCT04180215) assessed HB-201 monotherapy and HB-201 and HB-202 alternating 2-vector therapy intravenously with or without 1 intratumoral dose in HPV16+ cancers. An interim analysis looked at 38 patients with confirmed HPV16+ cancers. In total, 18 patients received HB-201 monotherapy, 9 received the monotherapy intravenously with or without 1 intratumoral dose and 11 patients received HB-201/HB-202 alternating therapy.

In an interview with Targeted Oncology^TM, Marshall Posner, MD, a professor of medicine, hematology and medical oncology at Mount Sinai, discusses the use of the HB-201 and HB-202 vaccines in patients with HPV16+ cancers.

TARGETED ONCOLOGY: Can you go over the safety, efficacy, and immunogenicity of arenavirus-based vectors HB-201 and HB-202 in patients with HPV16+ cancers?

POSNER: This is a first in human phase 1 trial with expansion cohorts, to occur later, of 2 vaccines. One is a lympho-choriomeningitis virus-based arenavirus vaccine and the other is a pichinde virus-based vaccine, both of which express the E6 and E7 proteins, and both are based on viruses infecting antigen presenting cells. The E6 and E7 proteins were going to be processed and presented to the immune system in the context of an inflammatory response to the virus. Neither of these viruses are human attacking viruses, so they won't cause any significant pathology in humans. And these were the phase one studies looking at the HB-201 vaccine by itself, and then alternating regimen with Hb-201 and HB-202, which has been shown in animal models to be actually synergistic in anti-tumor activity. This particular presentation is about the safety and potential efficacy of combining these vaccines with pembrolizumab. So, the later on trials will include pembrolizumab in the process, but this was an early attempt to see what pembrolizumab could do, but primarily to look at the safety.

We presented the first 3 patients who have progressed on the vaccines and subsequently had pembrolizumab added to the treatment. This was a modification of the original protocol to allow us to really perform the phase 1 study in an earlier fashion. All the patients who were on this particular cohort had prior checkpoint blockade inhibitor and/or other chemotherapies and checkpoint blockade inhibitors. So, this was a heavily pretreated group who had failed multiple rounds of therapy in the recurrent metastatic setting. I personally know 2 of the patients had a really extensive visceral involvement with the cancer. So, this was really a group of patients for whom you would expect to see side effects, other problems related to the tumor itself and not expect a response. And yet with them, we saw some stabilization of disease, we saw minimal impact of adding pembrolizumab. No treatment emergent adverse events that were concerning or that led to modification or reduction of dose for stopping the pembrolizumab and other treatment.

What we did see was stabilization of disease, some evidence of a response, but not robust. And we also saw no change in a robust up regulation of responsive T cells. In an L spot test, which involves stimulating the T cells from a peripheral blood with protein. The protein targets the antigen. What they saw in the initial study inpatients with the vaccine, was a big upregulation of both T cell responses and CDA responses specifically. In the addition of pembrolizumab, they did not see a further increase. They saw a maintenance or a slight reduction. So, it's unclear what that's about. But it does indicate that we already have robust responses, and they certainly weren't inhibited by adding the pembrolizumab in any significant fashion.

The results of the trial will allow us to move forward in the trial that we're doing by adding pembrolizumab to more patients. Moving forward, when we hit our recommended phase 2 dose of either the single vaccine or the double vaccine treatment, we added pembrolizumab. In the subsequent phase 1 and phase 2 expansion. I think the aim here is to go forward with a combination, rather than to do the expansion cohort with just the vaccine, but that's up to the company and not up to me. It proved to be reasonably tolerable. There was a good safety signal and a good signal of some evidence of at least clinical responsiveness in the patients. So that was the end result of the study.

What was the reasoning behind adding pembrolizumab to the HB-200 vaccines in this patient population?

There's some suggestion that given the patients don't make a robust response to HPV by itself, that adding pembrolizumab would boost the response obtained with a vaccine by blocking inhibitory signals in the tumors. That is going to take some more work, you're not going to see that early on in these kinds of trials. Although the data is suggested that it well, it's really a small number of patients. So, that's the rationale for doing that. It's possible that pembrolizumab isn't the right immune stimulant and that we need to simulate some other part of the immune system and I think as further studies go on, looking at the combination of pembrolizumab with other immune modulating drugs, that we'll see some changes that will suggest other agents to combine with the vaccines.

What is the mechanism of action of the HB-200 vaccines with pembrolizumab and without pembrolizumab?

The presumption is that the vaccines will enhance CDH stimulation. And you'll have activated CDA cells entering the tumor and killing the tumors based on their immune activation from the vaccine. Adding pembrolizumab would hopefully eliminate intertumoral, PD0-L1 and PD-1, inhibition of that immune response as well as inhibition of immune response with the T cells. So, those are the gross mechanisms of action. But really micro analysis of that is going to take some look at the material that the company has collected and some of the scientific laboratory investigation that they're doing to look at that. We're at the dawn of immunotherapy. I think the question goes right back to why do we only see a small fraction of patients responding to immunotherapy with head and neck cancer? Not as many as you would see, for example, with melanoma, but it's still a fabulous result. But the question is really basically why are HPV-negative and HPV-positive patients not responding and are their mechanisms the same or different? Do we need to really look different modulators to the immune system in these patients?

_REFERENCE:

_{Ho A, Posner M, Niu J, et al. First report of the safety/tolerability and preliminary antitumor activity of HB-201 and HB-202, an arenavirus-based cancer immunotherapy, in patients with HPV16+ cancers. Jour. Clin. Oncol. 2021;39(15):2502 doi: 10.1200/JCO.2021.39.15_suppl.2502.}