This story has been adapted from the STAT Report “The future of messenger RNA: Covid-19 vaccines are just the beginning.”
The unprecedented success of messenger RNA vaccines against the coronavirus is raising hopes that the technology could lead to new and better vaccines against a much older public health scourge: cancer.
In some ways, the challenge is similar: The aim of any vaccine is to focus the immune system’s response against a particular molecule, or antigen, whether that’s a piece of a virus or a protein that coats tumor cells. There’s one important difference, however: Cancer vaccines are generally treatments rather than preventative measures.
“The tumor cells are already there. And you have to build an army of immune cells which is big enough,” said Özlem Türeci, co-founder and chief medical officer of BioNTech, which has eight different cancer vaccines currently in clinical trials. “It’s a numbers game to conquer a tumor, which means you have to be able to induce very strong immune responses.”
Biotech companies are approaching this problem in two main ways: targeting antigens that are shared across patients and going after tailor-made targets. The former are “off-the-shelf” vaccines that could be used across patients, while the latter are bespoke vaccines.
The personalized approach starts by taking a sample of both a patient’s cancer cells and healthy tissue. Researchers then compare the DNA and RNA sequences of these healthy and cancerous samples to identify mutations they can target with a vaccine.
There are plenty of examples now in process, including a Phase 2 trial BioNTech started in October 2021 for colon cancer patients who’ve had their tumors surgically removed but still have cancer cells remaining, with bits of tumor DNA floating in their blood. The roughly 200-person randomized study is testing whether the vaccine improves disease-free survival compared with simply monitoring patients, which is the current standard.
Along similar lines, Massachusetts biotech Moderna is testing a personalized cancer vaccine strategy of its own in both Phase 1 and Phase 2 trials. The drug, known as mRNA-4157, delivers mRNA coding for up to 34 tumor antigens, and is being tested in combination with Merck’s PD-1 antibody, Keytruda, which strengthens anti-cancer immune responses.
In November 2020, Moderna announced initial Phase 1 findings from 10 patients with head and neck cancer and 17 with colon cancer. The results were mixed. Half the head and neck patients responded to the treatment, and doctors could no longer detect cancer in two of them. But none of the colon cancer patients responded.
The company is now expanding the study to include a total of 40 head and neck cancer patients, and to determine the best dose for a Phase 2 trial it has been slowly increasing the dose it is using. That Phase 2 study is a randomized trial in which 100 melanoma patients who’ve had their tumors removed but are at high risk for recurrence receive the experimental vaccine and Keytruda, while 50 participants get Keytruda alone.
Each strategy comes with pros and cons. “Off the shelf” vaccines that can be used in many patients are cheaper and can be administered more quickly. But a bespoke approach allows scientists to target a wider range of cancer antigens. And targeting multiple antigens decreases the odds that cancer cells will mutate in ways that make the vaccine useless, because the immune system will be attacking on multiple fronts. That makes personalized vaccines a better fit for fast-mutating cancers, according to Türeci.
But there’s no way to know for sure if a tailored or more generic approach will work better, which is why companies often test both approaches in parallel. For instance, BioNTech has trials of both strategies for melanoma, including one of BNT111, an mRNA cancer vaccine that codes for four melanoma-associated antigens in patients with advanced disease. That potential treatment is currently being tested in a Phase 2 clinical trial. And BioNTech is also running a Phase 2 study of BNT122, a personalized vaccine for melanoma patients with advanced disease who haven’t previously been treated.
Both BioNTech and Moderna identify potential vaccine targets by sequencing a cancer cell’s exome, the roughly 1% of the genome known to code for protein. But German biopharma company CureVac is instead reading whole genomes, driven by a growing recognition that the non-protein coding parts of the genome are far from “junk” DNA.
“Most of the differences between the cancer cell and the healthy cell when it comes to the antigens are encoded by what was then referred to as the junk DNA,” said Ronald Plasterk, CureVac’s senior vice president of innovation and science.
The company’s whole-genome approach, made feasible by the plummeting cost of DNA sequencing, is based on work by Frame Therapeutics, a Dutch biotech that CureVac acquired for about $34 million in June (Plasterk was Frame’s founder and CEO). The biotech is working on both fixed-antigen and personalized vaccines, though it hasn’t publicly disclosed which cancers or antigens are its targets.
CureVac is also working on ways to synthesize mRNA in teeny amounts to support its personalized vaccine work. In 2020, CureVac and Tesla (yes, the electric car company) announced a deal in which Tesla would develop small, portable mRNA “printers.”
There are plenty of challenges ahead, Plasterk said, from figuring out how to generate immune responses strong enough to make a dent in solid tumors to working out how best to combine cancer vaccines with the three current mainstays of cancer care: surgery, radiation, and chemotherapy. But he’s optimistic the many small steps companies are taking will help answer these and other outstanding questions.
“There’s a huge gap between what we know about cancer” and the current standard of care,” he said. “I think immunotherapy will be a full fourth pillar in treatment of cancer in the years to come.”