VB-10.16

Pictured: Vaccine bottles/iStock, May Lim Several cancer vaccine candidates are flying through clinical trials with promising results. Unlike traditional vaccines that aim to prevent a disease from occurring, therapeutic cancer vaccines train the patient’s immune system, enabling T cells to patrol the body for cancer cells and destroy them. Progress in personalized medicine has made it easier and much more affordable to sequence patient genomes, pull out unique cancer signatures and make vaccines encoding these neoantigens. BioSpace compiled a list of five cancer vaccines in mid- to late-stage development and sought insights from two experienced researchers on their respective merits. Moderna and Merck’s Melanoma Vaccine Generating possibly the most attention is Moderna and Merck’s mRNA-based vaccine for metastatic melanoma. In July, the partners announced a Phase III trial for the vaccine, dubbed mRNA-4157, which will be delivered alongside the immune checkpoint inhibitor Keytruda (pembrolizumab). This announcement was made following the release of positive Phase IIb results in April that showed patients treated with mRNA-4157 plus Keytruda had a 44% lower risk of cancer recurrence or death than patients treated with Keytruda alone. mRNA-4157 is made up of a single synthetic mRNA that can encode up to 34 neoantigens derived from patients’ distinct genetic cancer signatures. When translated, the neoantigens trigger the activation and multiplication of T cells, which surveil the body for cancer cells expressing them. The encouraging Phase IIb results also prompted the FDA to grant the vaccine Breakthrough Therapy Designation. Curiously, patients with both high and low tumor mutational burdens (TMBs) showed similar responses to the mRNA therapy. This counters historical correlations of high TMB and the success of immunotherapy, particularly for melanoma. Ryan Sullivan, a medical oncologist at the Dana-Farber Harvard Cancer Center who has served as the principal investigator on several clinical trials for cancer therapeutics, including one looking at the effectiveness of mRNA-4157 across TMB levels, posed the question, “Is there something about the vaccine that helps to overcome the lack of a TMB?” Sullivan said Merck and Moderna have expressed interest in investigating the link between TMB and therapeutic efficacy in Phase III. The trial, which will recruit 1089 participants, is expected to be completed in 2029. BioNTech’s Pancreatic Cancer Vaccine BioNTech announced in October that the first patient in a Phase II trial of autogene cevumeran, an mRNA vaccine against pancreatic ductal adrenal cancer (PDAC), had been treated. The vaccine, which consists of an mRNA encoding for up to 20 neoantigens tailor-made for different patients, is delivered alongside the immune checkpoint inhibitor atezolizumab. The open-label, randomized trial has two arms. In the first, patients are treated with a combination of the vaccine, atezolizumab and standard chemotherapy. These patients will be compared to a second arm of patients who receive only standard chemotherapy. The vaccine, jointly developed by BioNTech and Genentech, was previously tested against a host of solid tumors in a Phase I trial where it triggered a large cohort of neoantigen-specific T cells in PDAC patients, many of whom went for long periods without cancer recurrence. This is particularly important for PDAC, which has a high relapse rate and is notoriously difficult to treat. The Phase II trial will recruit 206 patients and is expected to be completed in 2029. “I think we’re all interested in some of the new epitope trials with pancreatic cancer just because it’s so universally deadly and difficult to treat,” said Zachary Hartman, an associate professor at Duke University School of Medicine who studies how to harness immune responses to treat cancer. In addition to PDAC, autogene cevumaren is being tested in Phase II trials for colorectal cancer and melanoma. Transgene’s Viral Vector-Based Vaccine French biotech Transgene announced promising results for its viral vector-based vaccine, TG4050, developed in partnership with NEC Corporation. The vaccine, which is currently in Phase I trials for ovarian cancer and HPV-negative head and neck cancer, has shown robust immune responses in patients. The ability to generate a strong immune response, especially in cancer patients who may already have weakened immune systems, is the first indicator that a cancer vaccine can be effective. Indeed, TG4050 has evoked T cell activity even in patients who are over 65 or have low circulating lymphocyte counts at baseline, Transgene CSO Eric Quéméneur told BioSpace in an email. Trial participants treated with the vaccine remained disease-free as of June 2023, and the company expects both studies to be completed in 2024. The vaccines, developed using Transgene’s trademark myvac platform, carry neoantigens selected by NEC’s AI-based system. The neoantigens are customized for each patient and reflect their unique cancer mutations, opening the door to treating many more types of cancer. “I think you can make an argument that virtually any tumor type might benefit from this type of vaccination,” Sullivan said. OSE’s Advanced NSCLC Vaccine In September, OSE Immunotherapeutics published positive results from a Phase III trial of its cancer vaccine for advanced non-small cell lung cancer (NSCLC). Branded Tedopi and approved for compassionate use in France, Italy and Spain, the vaccine is a mix of antigenic peptides meant to activate anti-tumor T cells. The antigens were selected because they are commonly expressed in patients with NSCLC and the HLA-A2 phenotype. Importantly, the 219 trial participants had already been treated with immune checkpoint inhibitors and chemotherapy but had either developed resistance to the former or had not responded to the latter. Participants treated with Tedopi had markedly better survival and quality of life than those who received standard chemotherapy. These results carry promise for patients who have exhausted conventional modes of treatment and do not have many remaining options. Tedopi is also being tested in Phase II trials for the treatment of PDAC and recurrent ovarian cancer. Nykode’s Cervical Cancer Candidate Norway–based Nykode Therapeutics in April announced positive results for the Phase IIa trial of its cervical cancer vaccine. The vaccine, VB10.16, was delivered to 52 trial participants in combination with atezolizumab. Patients who received the vaccine were tracked for one year and showed a median overall survival of 16.9 months. A second, larger trial of VB10.16 in cervical cancer is set to begin later this year. Nykode’s vaccine design is different from that of others on this list. VB10.16 is a plasmid DNA-based vaccine encoding a three-part Vaccibody. Of the three units, one is a collection of up to 20 neoantigens and the other is a targeting unit that attracts antigen-presenting cells (APC). Depending on the type of APC attracted, the vaccine can activate either T cells, which kill cells carrying the neoantigen, or B cells, which make antibodies against the neoantigen-bearing cells. Hartman stressed the importance of prioritizing both antibody and T cell responses to cancers. “Antibodies are kind of like the right arm of the immune system, and T cells might be the left arm, so to be an effective fighter you need both.” He added that most cancer vaccine studies tend to ignore antibody responses, which is “something that we would neglect at our own peril.” Both Hartman and Sullivan expressed optimism about current progress with cancer vaccines. “If these early trials are showing benefit, I think the sky’s the limit in terms of where we’re going with tumor vaccination,” Sullivan said. Sruthi S. Balakrishnan is a freelance academic editor, science writer and fact-checker based in Santa Barbara, California. She can be reached at sruthisb@sciscriber.com.