Many cancer vaccines have been studied, but thus far the search has been unsuccessful. Results from a new study suggest that the combination of a messenger (mRNA)-based personalized cancer vaccine (known as RO7198457) plus the PD-L1 inhibitor atezolizumab (Tecentriq) shows promise for the treatment of advanced cancer. The results of the phase 1b clinical trial were presented at the virtual 2020 American Association for Cancer Research (AACR) annual meeting.
This novel combination was well-tolerated and had a modest response rate of 8%, and approximately 50% of patients in the study had stable disease. The investigators emphasized that this combination therapy generated immunogenicity, noting that the treatment approach may be more effective in earlier stages of cancer.
“Many cancers are able to successfully avoid the immune system, and we are only starting to understand the myriad ways in which cancers can do this. Because many mutations are not shared between cancers, a personalized treatment approach that targets individual tumor neoantigens may be a viable immunotherapeutic strategy for numerous patients with cancer,” explained lead investigator Juanita S. Lopez, MB BChir, PhD, MRCP, Consultant Medical Oncologist, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, England.
“We saw that the combination was generally well-tolerated, and the approach induced an immune response in the majority of patients, including within the tumor,” she noted.
RO7198457 is an mRNA-based vaccine that is specially manufactured for each patient. Tumor and blood samples are sequenced to identify tumor-specific neoantigens, which should be recognized as foreign by the immune system. After selecting up to 20 tumor neoantigens, the corresponding mRNA is generated forming the backbone of the vaccine, which is then encapsulated in a liposomal formulation to enable intravenous administration, Dr Lopez said.
“These authors used a novel design combining a neoantigen RNA-based vaccine unique to each patient with atezolizumab. This study differs from other neoantigen vaccine studies in the schedule of giving the vaccine with an immune checkpoint inhibitor,” said AACR Past President Elaine R. Mardis, PhD, FAACR, Co-Executive Director, Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH.
“Other studies have used different sequencing, whereas this study gives the vaccine with the PD-1 agent, at intervals. We really don’t know the best sequence when combining the vaccine approach with an immune checkpoint inhibitor, and it is important to have these trials,” said Dr Mardis. She commented on this study at a premeeting press cast; it was 1 of 5 abstracts that were highlighted at the press cast.
First, the investigators looked at the vaccine as monotherapy and determined that it was safe but did not have strong activity. They then decided to combine the vaccine with a PD-L1 inhibitor to boost the immune response.
The phase 1b study enrolled 144 patients with advanced solid tumors—including non–small-cell lung cancer (NSCLC), melanoma, triple-negative breast cancer, and urothelial cancer—and a median of 3 previous therapies. More than 90% of the patients had low levels of PD-L1 expression in tumor-cell assays.
The vaccine was administered in weekly doses for the first 6 weeks, and the next 2 doses were given every 2 weeks. Atezolizumab 1200 mg was given on day 1 of each 21-day cycle. A booster dose of the vaccine was given during the seventh cycle of atezolizumab, along with a maintenance dose of the vaccine every 24 weeks after the induction phase.
The majority of adverse events were grade 1 or 2. Infusion-related reactions and cytokine release syndrome were reported in 15% of the patients, but these were transient and reversible.
No dose-limiting adverse events were reported. A total of 7 (5%) patients discontinued treatment as a result of treatment-related adverse events.
Of 108 evaluable patients, 9 had a response, for an overall response rate of 8%, which included 1 patient with colorectal cancer who had a complete response; in addition, 53 (49%) patients had stable disease.
The evaluation of peripheral blood showed that 73% of the patients had neoantigen-specific T-cell responses induced by the vaccine. A total of 46 patients had ex vivo responses that were mostly CD4 and CD8 T-cells.
“In this trial, we show that we were able to generate tumor-specific immune responses in the majority of evaluable patients using a personalized cancer vaccine approach in combination with immune checkpoint blockade. While the clinical response rate overall was low, this is likely because many of the patients treated in our study had very advanced disease and were heavily pretreated,” Dr Lopez said.
The combination strategy will be studied in earlier stages of cancer and in randomized phase 2 trials of patients with melanoma and early-stage NSCLC.
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