In 2019, Cancer Therapy Advisor spoke with virologist Jennifer Altomonte, MD, principal investigator at Klinik und Poliklinik für Innere Medizin II in Munich, Germany, about the phase 3 HCC data. At that time, Dr Altomonte suggested that Pexa-Vec may have failed because HCC — known to have an immunosuppressive microenvironment — was a difficult target. “Less is known about the immunosuppressive environment of the kidneys,” she said in reaction to the phase 1b trial results, “but there seems to be clinical success with ICI for RCC, and there is a strong rationale for combining therapeutics (eg, anti–PD-1) with oncolytic viruses.”
Zong Sheng Guo, PhD, of the University of Pittsburgh School of Medicine, who published a review article in 2019 on VV-mediated cancer immunotherapy, explained to this publication that RCC might indeed be an easy target. “RCC is considered to be one of the most immunogenic types of cancers,” he said. It was not surprising to Dr Guo to see a relatively good clinical response from the combination of an oncolytic virus and an anti–PD-1 antibody with tolerable toxicity; similar results have been found with this combination in patients with advanced melanoma — another immunogenic type of cancer.
Nonetheless, the phase 1b study does leave several questions unanswered, said Dr Guo. “The obvious scientific question, intriguing to most readers in the field, is why some patients responded, while others not?”
Further, Guo and Altomonte agreed that biopsy results before and after treatment would be important. “It is unclear from the abstract whether biopsies were taken from the patients at any time after therapy,” said Altomonte. “If so, the investigators should certainly do analysis to investigate whether there is evidence of virus replication, immune cell infiltration, etc, within the tumor.”
Scott Tykodi, MD, PhD, echoed the concerns of Drs Guo and Altomonte, and questioned whether Pexa-Vec, cemiplimab, or the combination of the 2 therapies contributed to the positive outcomes in the phase 1b trial. “As an anti–PD-1 antibody, cemiplimab would be expected to have significant antitumor activity for RCC, analogous to nivolumab or pembrolizumab.” He added, “While Pexa-Vec, in principle, might be an interesting approach if it had selective RCC tropism, the burden of proof is on the study team to show evidence that Pexa-Vec is actually infecting tumor and delivering GM-CSF [granulocyte-macrophage colony-stimulating factor] to the tumor microenvironment.”
In addition to these questions, Dr Tykodi, director of kidney cancer research and associate professor at the University of Washington, Seattle, said he is concerned about the long-term efficacy of VV. “Patients quickly develop a serological response to vaccinia, so serial rechallenge with Pexa-Vec given systemically is likely to be compromised by neutralizing antibodies.”
Dr Rha and colleagues are working toward answering some of these questions. At AACR, Dr Rha reported that the phase 1b trial is ongoing, with plans to:3
- Assess correlations between tumor regression and Pexa-Vec–induced anti-vaccinia and antitumor T-cell responses
- Investigate response rates in patients who were added to the second stage of cohort C
- Analyze results of another cohort receiving intratumoral Pexa-Vec and cemiplimab
- Evaluate patients (in a newly formed cohort D) who progressed while receiving an immune checkpoint inhibitor.
- Guo ZS, Lu B, Guo Z, et al. Vaccinia virus-mediated cancer immunotherapy: cancer vaccines and oncolytics. J Immunother Cancer. 2019;7:6.
- Tweet by Nazli Dizman (@NazliDizman).”Ph1 study presented by Dr. Sun Young Rha et al …” https://twitter.com/NazliDizman/status/1254838015622410241. Published April 27, 2020 at 2:21 PM. Accessed May 27, 2020.
- Rha SY, Merchan J, Oh SY, et al. A phase 1b study of recombinant vaccinia virus in combination with immune checkpoint inhibition (ICI) in advanced renal cell carcinoma (RCC). Poster presented at: American Association for Cancer Research (AACR) Virtual Annual Meeting I 2020; April 27-28, 2020.