Cancer “vaccines” enter the neoantigen stage

The development of so-called cancer vaccines has endured countless clinical setbacks, but biopharma has continued work undeterred. This week saw the field record one of its largest windfalls, with Merck & Co handing across $250m to Moderna to exercise an option over the latter’s mRNA-4157.

Still, mRNA-4157 is no ordinary cancer “vaccine” – it is a personalised mRNA therapeutic created on demand based on the neoantigens present in each patient’s tumour. Such neoantigen-based immunotherapies are the latest incarnation of work that has already seen Roche and Johnson & Johnson buy in, and in which Gritstone is perhaps the most notable small player.

Merck and Moderna have in fact been working together since 2016, and the Keynote-942 phase 2 study combines mRNA-4157 with Keytruda. However, it is only now that Merck has formally opted in to develop mRNA-4157 and similar personalised therapies.

With Moderna shares up 13% so far this week, investors appear to welcome the fact that the group has a plan beyond Covid vaccines, as well as perhaps guessing that Merck has already had a sneak preview of Keynote-942 – the trial is formally due to yield preliminary data in the current quarter – and likes what it has seen.

If this is true Moderna will have done better than Roche. The Swiss group’s autogene cevumeran, an mRNA therapy based on the same concept as mRNA-4157, showed modest activity in a trial highlighted at AACR 2020, though data from an academic study of pancreatic cancer in the adjuvant setting, at this year’s Asco, seemed more promising.

Vaccines?

In a sense the concept of cancer vaccines, coined at least 30 years ago, is a misnomer, since none of these projects would work as a preventative. Rather, they aim to raise an immune response in the therapeutic setting.

The original incarnation, against known tumour antigens, recorded one failure after another, the most notorious of which was the 2014 blow-up of GSK’s Mage-A3 project. Provenge did make it to market, but despite being a clinical success its maker, Dendreon, ended up entering bankruptcy protection.

The focus on neoantigens offers fresh promise, however. Rather than targeting known tumour-associated antigens like Mage-A3, which may or may not be present in a given cancer, these therapies start with an analysis of the specific mutations and sub-mutations in each patient’s tumour, with sequencing then performed to identify a given number of such neoantigens.

Naturally, this is extremely complex commercially, as a therapeutic is then raised on a patient-by-patient basis, and injected to elicit an immune response. In the case of autogene cevumeran and mRNA-4157 this comprises mRNA encapsulated in lipid nanoparticles, but there are other means to do this, including delivering DNA or peptides via plasmids or virus vectors.

Roche has in fact made two notable forays into the neoantigen field. Autogene cevumeran is the result of a 2016 deal with Biontech, while a second tie-up, with Norway’s Vaccibody (now known as Nykode) gave the Swiss firm co-development rights to a DNA plasmid-based project, VB10.NEO. Another private biotech, Italy’s Nouscom, boasts a deal with J&J.

Meanwhile, Gritstone is notable for being a small-cap player with a major focus on mRNA-based neoantigen therapies. Last year it saw sufficient positive signals in a small mid-stage trial of a project coded Granite-001 to begin a registrational phase 2/3 study in colorectal cancer, and could thus be considered the most advanced player here.

Granite-001, like a second Gritstone project, Slate-001, uses a two-stage approach, first delivering a priming adenoviral vector and then a self-amplifying mRNA booster.

Another mRNA company, Curevac, had been working on an early-generation immunotherapy, CV9104, but this failed in the clinic. In June it bought the private business Frame Cancer Therapeutics for just €32m ($31m) in stock, and through this gained rights to FRAME-001, a neoantigen-based peptide project in phase 2 for NSCLC.

Cell therapies

Adoptive cell therapies are also in development against neoantigens, though at the moment only a handful are in the clinic, and they probably present an even greater level of complexity.

Biontech acquired Neon Therapeutics in a 2020 deal worth $67m in stock, and through this gained BNT221, which takes the tumour-infiltrating lymphocyte (TIL) approach a stage further. Rather than simply expanding a patient’s TILs before reinfusing them, this sequences the tumour and generates a population of T cells known to be reactive specifically against the neoantigens present in each tumour.

This is conceptually similar to ATL001, the lead project in development by Achilles Therapeutics, another group that has struggled with a falling valuation since going public in 2021.

At what might be the most revolutionary end of the spectrum is the NCI’s Dr Steve Rosenberg’s approach, which aims to generate a different engineered T-cell therapy for each patient based on an analysis of the neoantigens present in their tumour. This was licensed to Ziopharm in 2019 for use with the latter’s Sleeping Beauty transposon system.

A similar approach is being taken by the private start-up Pact Pharma, which got funding from none other than Arie Belldegrun's Vida Ventures. However, both have struggled: Ziopharm underwent a C-suite overhaul and changed its name to Alaunos, while Pact this month had to effect an asset sale to a CRO, and its clinical study has suspended enrolment.

Turning some of these groundbreaking approaches into a commercially viable product will not be easy, but Merck buying into Moderna shows that pharma thinks it is up to the task.