Meet the Cancer Commandos

Cancer vaccines are an exciting avenue in drug development – one that has been further fuelled by developments in mRNA. Why is this? Five experts recently explained how cancer vaccines work. And then, in part II, they outlined the challenges for the field and how we can separate hype from reality. Here, we ask those same five experts to tell us what their companies are doing in the cancer vaccine space.

OSE Immunotherapeutics
 

OSE Immunotherapeutics focuses on therapies that seek to harness the immune system.

There are several products in its pipeline, including an off-the-shelf and ready-to-use cancer vaccine called Tedopi, which is based on nine optimized CD8 T-cell epitopes designed to break tolerance against five selected tumor-associated antigens. It has demonstrated positive results as a monotherapy in a first phase III randomized trial in NSCLC patients after acquired resistance to anti-PD(L)1 treatment.

“Based on the promising clinical benefit and good safety profile we have seen with Tedopi in NSCLC patients, we are advancing the clinical development into second line through a confirmatory pivotal randomized phase III in NSCLC,” says Nicolas Poirier, CEO of OSE Immunotherapeutics. “We are also conducting several phase II studies in combination with anti-PD1 or chemotherapy in NSCLC, ovarian cancer and pancreatic cancer.”

In April 2024, the company received €48.4 million in public funding from the plan “France 2030” to support a phase III clinical trial of Tedopi in second line treatment in HLA-A2 positive NSCL patients with secondary (acquired) resistance to anti-PD-(L)1 immunotherapy. The company also received €1.5 million funding from Bpifrance in June 2023 to support the development of a companion diagnostic test (HLA-A2) for Tedopi.

Candel Therapeutics
 

Candel is a clinical stage biopharmaceutical company focused on developing off-the-shelf multimodal biological immunotherapies that elicit an individualized, systemic anti-tumor immune response to help patients fight cancer. The company has established two clinical stage multimodal biological immunotherapy platforms based on novel, genetically modified adenovirus and herpes simplex virus (HSV) gene constructs, respectively. CAN-2409 is the lead product candidate from the adenovirus platform and is currently in ongoing clinical trials in non-small cell lung cancer (NSCLC) (phase 2), borderline resectable PDAC (phase II), and localized, non-metastatic prostate cancer (phase II and III). CAN-3110 is the lead product candidate from the HSV platform and is currently in an ongoing investigator-sponsored phase 1b clinical trial in recurrent high-grade glioma (rHGG). Finally, Candel’s enLIGHTEN Discovery platform is a systematic, iterative HSV-based discovery platform leveraging human biology and advanced analytics to create new viral immunotherapies for solid tumors.

The company also has established two clinical stage viral immunotherapy platforms based on novel, genetically modified adenovirus and herpes simplex virus (HSV) gene constructs, respectively. 

Paul-Peter Tak, CEO of Candel Therapeutics, says: “CAN-2409 is the lead product candidate from the adenovirus platform and is currently in ongoing clinical trials in NSCLC (phase II), pancreatic cancer (phase II), and localized, non-metastatic prostate cancer (phase II and phase III). CAN-3110 is the lead product candidate from the HSV platform and is currently in an ongoing clinical trial in recurrent high-grade glioma. We believe we have established proof of mechanism in each indication that we are currently pursuing. In October 2023, we published in Nature encouraging data from a Phase 1 trial using CAN-3110 in a prototypic therapy-resistant form of cancer – recurrent high-grade glioma (Al Ling et al., Nature (2023); DOI: 10.1038/s41586-023-06623-2).”

CureVac

CureVac has integrated novel antigen discovery technologies from the acquisition of Frame Cancer Therapeutics into its R&D – and expanded this with a partnership with myNEO. “Based on both innovative platform technologies, we apply a combination of whole genome sequencing, long/short-read RNA sequencing, and bioinformatics to map and rank the genetic alterations of the tumor and deduct highly immunogenic antigens that haven’t been used in immune-oncology so far,” explains Myriam Mendila, Chief Development Officer of CureVac. “Together with our second-generation mRNA backbone, we will use these new antigens to drive the development of novel cancer vaccine candidates. We’ll be focusing on the development of off-the-shelf cancer vaccines – based on tumor antigens shared across different cancer indications – and fully personalized cancer vaccines based on a patient’s individual tumor genomic profile.”

In June 2023, CureVac entered the execution phase of its cancer vaccine development strategy with the start of a phase I study in patients with resected glioblastoma. The tested vaccine candidate, CVGBM, features a single unmodified mRNA construct encoding eight epitopes derived from known tumor-associated antigens with demonstrated relevance in glioblastoma.

“One way we are trying to address the second major challenge to cancer vaccine development and deliver small quantities of candidate cancer mRNA vaccines as quickly as possible to patients – especially in a personalized therapy approach – is by using The RNA Printer,” adds Mendila. “The RNA Printer is CureVac’s automated end-to-end system that includes all main steps for the manufacturing of GMP-grade mRNA vaccines and therapeutics. It is designed for smaller scale quantities that makes it an optimal solution for the rapid and flexible provision of therapeutic cancer vaccines for either a smaller group of patients or even one individual patient. The technology is currently in regulatory approval.”

Ultimovacs
 

Ultimovacs is developing a vaccine, UV1, against the universal cancer antigen telomerase. The vaccine consists of three long synthetic peptides, representing 60 amino acids of the reverse transcriptase subunit of human telomerase. The peptides contain several CD4 and CD8 epitopes, shown to be promiscuous in terms of human leukocyte antigen (HLA) allele type for presentation. It is, therefore, not required to perform HLA pre-screening of patients to achieve broad population coverage of the vaccine. UV1 is administered by repeated intradermal injections together with the immune-modulator GM-CSF.

Data from the first randomized phase II trial with UV1 for second-line treatment in patients with malignant mesothelioma was presented at ESMO 2023. The data showed that UV1, in combination with ipilimumab and nivolumab, demonstrated a statistically significant and clinically meaningful improvement in overall survival versus ipilimumab and nivolumab alone, a key secondary endpoint. No additional safety concerns were reported from the UV1 treatment. UV1 plus ipilimumab and nivolumab improved overall survival, reducing the risk of death by 27 percent and median overall survival was 15.4 months for UV1 plus ipilimumab and nivolumab versus 11.1 months for ipilimumab and nivolumab alone.

TransImmune
 

Transimmune CEO Justin Duckworth describes the company as operating at the “nexus of vaccination and cell therapy.” He says, “We take the view that to unleash the full potential of the immune network, we must directly educate it in the manner it evolved to receive instruction. This means making and programming physiologic dendritic cells – a rare, activated form of antigen presenting cells. Although engaging dendritic cells directly is not new, the ability to engage truly physiologic dendritic cells is a recent development.”

For 50 years, Duckworth says the industry has used highly unphysiological methods to make dendritic cells that have led to suboptimal potency, unsustainable costs, and ultimately clinical disappointment. Transimmune is trying to solve these problems using dendritic cells made in the same way the human body makes them in vivo. 

The discovery at the heart of the company’s technology platform was made by founder Richard Edelson when he sought to understand how an extracorporeal chemotherapy he had invented in the 1980s (extracorporeal photopheresis; “ECP”) was curing cutaneous T cell lymphoma (“CTCL”) patients of their previously lethal cancers. Of the first five patients he treated, three saw complete responses, and even cures, despite the therapy only reducing the malignant T cell burden by about 5 percent. Years of research into understanding this extraordinary result uncovered that the ECP process was inadvertently making a crude immunotherapy. The conditions inside the extracorporeal device enabled platelets to activate monocytes to become dendritic cells, just as happens in vivo in response to a pathogenic threat. 

“In retrospect, Provenge had been beaten to market by an unappreciated, potent cancer vaccine that was masquerading as chemotherapy. In ECP for CTCL patients, the full array of cancer antigens was being readily provided to that patient’s physiologic dendritic cells, which successfully extract, sort, and present precisely the same tumor antigens to which that patient’s T cells can respond, thereby producing clinical results,” says Duckworth.

Transimmune’s technology has now been successfully applied preclinically, using its revised principles of ECP, to a range of solid cancers, including melanoma, ovarian, and colorectal cancer. The company has also been boosted by the Bill and Melinda Gates Foundation. “In 2021, the Foundation became interested in how our dendritic cells can potentiate mRNA vaccines and after an early grant have now followed through in 2023 with an investment in the company, focusing on infectious disease applications. Following this endorsement, our technology was honored to be included as a major component of the inaugural $25 million ARPA-H grant award, won by consortium partner Emory University. This grant is part of President Biden’s new Cancer Moonshot initiative and will focus on Transimmune’s dendritic cells reprogramming immunity in cancer and autoimmune disease,” says Duckworth.