For decades, researchers have worked to create drugs that teach the immune system to kill cancer cells the way traditional vaccines attack viruses. But while cancer vaccines have shown flashes of promise and a few have made it to market, it’s been a long and bumpy road, according to James Drew, director of content strategy for Citeline, in an email.
“The first therapeutic cancer vaccine approval in the U.S. was back in 2010,” he said, referring to Dendreon Pharmaceuticals’ prostate cancer treatment Provenge. “Since then, a series of late-stage trial failures by other cancer vaccine products have tempered expectations.”
But new scientific insights into tumor immunology and advances in mRNA technology are turning the tide, and oncological vaccines are finally gaining traction.
“The number of cancer vaccines in active preclinical and clinical development has almost doubled in the past 15 years, now sitting at over 350 unique therapies globally,” Drew said. There are more than 400 ongoing trials and more than 200 in the works, according to Citeline data.
Immunotherapy evolution
Therapeutic cancer vaccines differ from more traditional vaccines such as the human papillomavirus or the hepatitis B shots that prevent cancer by mitigating related viral threats. Instead, they teach the body to recognize specific antigens only expressed by cancer cells — otherwise, cancer cells avoid detection by masking those antigens.
“Generally, tumors with high mutation rates produce a lot of these neoantigens and so have been a key area of focus for drug development,” Drew said.
Companies like Merck & Co. and Moderna, as well as smaller biotechs, are developing options for 46 different cancers. About 20% of drugs target non-small cell lung cancer, and late-stage trials include options for melanoma, breast, pancreatic and brain cancers, according to Citeline.
“Interest from pharma and biotech is there, and we can expect these therapies to play an increasing role in treatment regimes in the second half of this decade."
James Drew
Director, content strategy, Citeline
While immune checkpoint inhibitors prime the immune system to fight cancer, therapeutic cancer vaccines train the body to continue recognizing cancer antigens and halt recurrence. And because of the potential symbiotic relationship between the therapies, companies are increasingly pairing vaccine technology with checkpoint inhibitors — like Merck’s Keytruda or Bristol Myers Squibb’s Opdivo, for instance — to boost efficacy.
“[Checkpoint inhibitors] dampen the immunosuppressive tumor environment, which in theory could improve the efficacy of a cancer vaccine,” Drew said. “In this context, cancer vaccines have great potential to improve response and reduce relapse rates in patients with tumors that respond to other immunotherapies.” A recent phase 1 kidney cancer trial at Dana Farber Cancer Institute showed early promise with a personalized vaccine given to patients with late-stage renal cell carcinoma. Among the nine patients in the trial, the median cancer-free rate was 35 months.
Another small trial of a personalized mRNA vaccine saw half of the 16 participants mount a lasting immune response aimed at keeping pancreatic cancer at bay after surgery. Six of the eight responders remained cancer-free in the study period.
Early victories, new starts
The FDA has already approved two antigen-targeting cancer vaccines — Provenge, which targets metastatic prostate cancer, and Imlygic, for metastatic melanoma. Two other similar FDA-approved options that use a different mechanism are Bacillus Calmette-Guérin and Adstiladrin for bladder cancer.
And there are many more in the pipeline. Among the more promising contenders are Merck and Moderna’s mRNA-4157 now in phase 3 in combination with Keytruda for melanoma, Drew said.
It’s also in testing for NSCLC, bladder and renal cancer. Other late-stage options include IO Biotech’s IO102-IO103 for melanoma, Polynoma’s seviprotimut-L also for melanoma, and Zeltherva from Sellas Life Sciences in phase 3 for acute myeloid leukemia.
Roadblocks ahead
Despite theoretical promise, especially when it’s personalized to the patient, can be costly, difficult and time-consuming to make.
“Off-the shelf products use neoantigens widely expressed in certain tumor types and could have more widespread utility, but proving strong efficacy could be a challenge,” Drew said.
But scientists have been hamstrung by an ongoing struggle to find the right antigens.
“Ideal candidates are highly expressed only in tumor cells, invoke strong and rapid dendritic and T cell responses, and have limited off-target effects,” he said. “But finding these among the thousands of candidates is a needle-in-the-haystack exercise.”
Companies are turning to AI to speed up the search.
Scientists also need to overcome tumor-related hurdles, namely their ability to outwit and suppress the immune system. However, work continues, and hopes are high that investigational vaccines will one day give patients new options.
“I’d say the interest from pharma and biotech is there, and we can expect these therapies to play an increasing role in treatment regimes in the second half of this decade,” Drew said.
