Cancer Vaccines’ Promise

Immune System, Mount Up

Much of the excitement around cancer vaccines stems from recent advances in vaccine technology, specifically the mRNA platform.

The advances were hard-earned, spurred on by the spectacular success of the COVID-19 vaccines. By leveraging research and development into mRNA vaccines originally geared toward cancer, companies managed to produce highly effective immunizations against COVID-19 in less than a year — an unprecedentedly short turnaround time for a brand new vaccine.

“The COVID experience has given cancer vaccine researchers a lot of reason for enthusiasm,” says Dr. Wolchok.

Short for “messenger RNA,” mRNA is a foundational molecule found in all cells. mRNA conveys instructions from genetic material to ultimately make proteins, the workhorses of biology. Proteins and other substances that elicit an immune response are known as antigens, and certain antigens occurring on the surfaces of pathogens — and critically on cancer cells, as well — are distinct from those displayed by noncancerous cells. Some cancer vaccines are accordingly being designed to put the immune system on high alert for uniquely cancer-connected antigens.

Toward this end, Dr. Wolchok and other Weill Cornell Medicine researchers are working in the area of personalized cancer vaccines — so named because they are custom-tailored to target the specific “neoantigens” that occur only on individual patient’s cancerous cells.

To identify neoantigens, researchers first obtain samples of a patient’s tumor, usually through surgery, and then genetically sequence the malignant cells. Just 10 years ago, the time and cost required to sequence tumor cells was prohibitive. But today the task can be completed in weeks for a few thousand dollars.

“With neoantigen information that we can now pretty quickly and inexpensively obtain, a vaccine can be manufactured in short order that is highly targeted to an individual person’s tumor mutation landscape,” says Dr. Wolchok.

A recent study, led by researchers at Memorial Sloan Kettering Cancer Center, speaks to the promise of this approach. The study centered on pancreatic ductal adenocarcinoma (PDAC), one of the deadliest cancers that kills nearly 90% of patients within five years of diagnosis. Sixteen PDAC patients received personalized mRNA vaccines, which included up to 20 neoantigens isolated on surgically removed pancreatic cancer tumors.

Half of the vaccinated patients exhibited strong neoantigen-targeting T cell generation, as intended. T cells are critical players in immune response, both as “helper” CD4 T cells that stimulate production of antigen-targeting antibodies to neutralize cancer cells, and as “killer” CD8 T cells that — as their name suggests — directly do the deed themselves.

Remarkably, 18 months later, the eight therapy-responsive patients showed no recurrence of their pancreatic cancer. Also remarkably, the time between surgery to first vaccine dose averaged only nine weeks.

“The rapid production aspects of mRNA vaccines, as well as formulations that make them so immunogenic, are quite attractive,” says Dr. Wolchok, who with Dr. Merghoub was an author on the study.

Similarly promising early results with mRNA vaccines have also been reported in patients with high risk of recurrent melanoma, the deadliest form of skin cancer, and for which Dr. Wolchok has been instrumental in establishing immunotherapy as a novel form of treatment.

One major challenge researchers face is identifying the best neoantigens for intensive vaccine development. The process is made difficult by cancerous cells often harboring dozens, if not hundreds, of neoantigen-sprouting mutations.

“Once we’ve sequenced someone’s tumor DNA, we still need to know which of the hundreds of mutations gives rise to a target,” says Dr. Wolchok. “In that area, we are still finding our way.” 

Common Targets

To help accelerate neoantigen quality assessment, scientists — including those at Weill Cornell Medicine’s Department of Pathology & Laboratory Medicine and the Englander Institute for Precision Medicine — are turning to computational biology, which brings together Big Data and ultrafast sequencing with tools such as artificial intelligence and machine learning.

The hope is that not only will clear neoantigen immune system objectives regularly come to the fore, but also deeper characterization of “shared antigens” that present across many patients’ tumors.

Researchers have already made significant headway in identifying and increasingly targeting these common cancer antigens. Unlike with neoantigens, which require bespoke vaccines after biopsy or surgery, shared antigen vaccines can be “off the shelf,” meaning generically formulated for prevailing immunogenic tumor features, less expensive to produce, and immediately available.

“An off-the-shelf cancer vaccine is ideal because you could have the right vaccine at the right time and that applies to everyone,” says Dr. Merghoub, who with Dr. Wolchok published a study last year about a potential shared antigen for a class of blood cancers called myeloproliferative disorders that is an attractive vaccine candidate.

Another example of an off-the-shelf, shared antigen vaccine is the novel drug that Stacey Haglund is receiving through the KISIMA-01 trial. Called ATP128, the vaccine primes the immune system against three antigens commonly expressed by colorectal cancers. To reduce the ability of cancer cells bearing these antigens to “hide” from the immune system, Haglund and other patients also receive an immune checkpoint inhibitor drug. Because cancer cells display the same immunological “off” switches as normal cells, immune checkpoint inhibitor drugs prevent T cells from receiving this “off” signal, thus equipping them to attack malignant cells (though at the risk of collaterally damaging healthy tissues).

Approved for use in humans for over a decade now, immune checkpoint inhibitors will play a critical role in realizing the full potential of cancer vaccines, says Dr. Merghoub, whose research includes finding ways to enhance inhibitor efficacy.

As a further case in point, vaccines and immune checkpoint inhibitors working together are being explored in an ongoing clinical trial for which Dr. Shah also serves as principal investigator. The trial centers on patients with inoperable or metastatic colorectal cancers whose malignant disease is driven by mutations in their DNA mismatch repair system’s genes, which fix naturally occurring, random DNA damage. Researchers liken the condition to having a broken “autocorrect” for one’s own DNA. “Because of defects in DNA repair, these tumors end up having a lot of mutations,” Dr. Shah explains. “Those mutations create neoantigens — new proteins that the immune system can recognize.”

In the subset of colorectal cancer patients affected by this phenomenon, their neoantigens display defined patterns, meaning that ultimately an off-the-shelf, shared antigen approach could be effective. The novel polyvalent vaccine at the heart of the trial targets the 50 most common mutated neoantigens, covering about 95% of these patients.

The hope is that the vaccine will augment the immune checkpoint inhibitor therapy, which on its own extends the lives of only about half of patients in this cohort who receive it.

“Through this clinical trial and others, we feel fortunate to be able to offer therapies to patients that are novel and cutting-edge,” says Dr. Shah.

Nipping Cancers in the Bud

Arguably even better than vaccines to treat active cancer would be vaccines that squash malignancies from the get-go, when only a handful of cells — or even a single cell — have gone haywire.

“Cancers are at their most vulnerable when they’re only a few cells and have not established a tumor environment that feeds the cancer and suppresses the immune system,” says Dr. Steven Lipkin, a professor of medicine, genetic medicine and the Gladys and Roland Harriman Professor of Medicine, who works on cancer vaccine development for patients with DNA mismatch repair mutations and helped design the colorectal cancer study Dr. Shah is leading.

Two vaccines that effectively prevent cancer caused by viruses — the hepatitis B virus (HBV) and human papilloma virus (HPV) — have been widely used for many years. Unlike the new immunotherapeutic generation of cancer vaccines, these vaccines empower the immune system against infectious entities known to trigger mutations in cells that vastly increase cancer risk.

According to the CDC, chronic HBV infections are linked to over half of all liver cancer diagnoses worldwide, while HPV causes more than 90% of anal and cervical cancers, around 70% of vaginal and vulvar cancers, and greater than 60% of penile cancers. Since vaccine rollouts, incidence of cancers related to these infections has dropped dramatically.

Researchers aim to build on this progress by cultivating the immune system to weed out cells showing early signs of malignancy well before they mutate enough to start evading immune surveillance.

To this end, Dr. Lipkin and Dr. Nasser Altorki recently received a $5.7 million grant from the National Cancer Institute to develop new cancer mRNA vaccine models, with the goal of entering clinical trials in five years.

Dr. Lipkin’s research focuses on Lynch syndrome, an inherited DNA mismatch repair deficiency condition. Afflicting about 1 in 280 Americans, Lynch syndrome is the most common genetic predisposition for gastrointestinal cancers, especially colorectal cancer.

Dr. Lipkin and colleagues are working on identifying the most prominent shared antigens displayed by Lynch syndrome-driven cancers and honing an mRNA vaccine platform to galvanize immune system cells accordingly.

Dr. Altorki’s vaccine research focuses on stopping precancerous lung lesions — known as lung non-solid nodule (NSN) premalignant neoplasms — before they progress to full-blown lung cancer. At present, the only treatment for these lesions is to surgically remove them. Yet this procedure can only be done when the lesions appear at lung edges, which often is not the case.

“Many people have multiple lesions, so that’s why you want to find a nonsurgical treatment,” says Dr. Altorki, professor of cardiothoracic surgery and the David B. Skinner, M.D. Professor of Thoracic Surgery at Weill Cornell Medicine, and director of the Division of Thoracic Surgery at NewYork-Presbyterian/Weill Cornell Medical Center.

In ongoing preclinical characterization and development, Dr. Altorki is working alongside Dr. Timothy McGraw, professor of biochemistry and of biochemistry in cardiothoracic surgery, and Dr. Vivek Mittal, professor of cell and developmental biology in cardiothoracic surgery, professor of cell and developmental biology and the Ford–Isom Research Professor of Cardiothoracic Surgery. Dr. McGraw is gauging how certain lung cells help regulate local immune response in the context of cancer, while Dr. Mittal’s lab has created a preclinical model of premalignant lung cancer that will be essential for the early testing of vaccines against certain neo- and shared antigens.

“We have all the building blocks in place and are ready to move forward,” says Dr. Altorki.

‘Seeing’ Cancer as ‘Evil’

Fundamental science that could likewise pave the way for new cancer vaccines involves the skin. New treatments for skin cancer are needed, given that more people develop this disease than all other cancers combined, including one in five Americans by the age of 70, and with the deadliest form, melanoma, spiking in incidence.

But our skin has deeper importance as an immunologically unique and complex area, says Dr. Niroshana Anandasabapathy, an associate professor of dermatology and of dermatology in microbiology and immunology. The largest organ of the body, skin serves as the main barrier between our internal environment and the external world. Standing guard, our skin hosts twice as many immune cells as our blood.

Because of the rich immune responses that skin can generate, the tissue layer looks highly promising for formulating both therapeutic and preventative cancer vaccines, regardless of the tissue type in which the cancer happens to originate. One key cell Dr. Anandasabapathy and colleagues are investigating is the dendritic cell type. Besides the skin, these cells occur in the “spaces” where the external environment interfaces with our body, including the lungs and gastrointestinal tract — the deadliest tissue sites of origin for cancer. By acting as special antigen-presenting cells for training T cells to deal with foreign entities, dendritic cells have a frontline role in immune surveillance and anti-tumor activity throughout the body.

“You can think of dendritic cells as generals in the immune army; they tell immune cells to stay tolerant to self or to go kill,” says Dr. Anandasabapathy. “Our hope is to better understand this population of dendritic cells, how they ‘see’ cancers, and to develop a vaccine that enhances their discernment of ‘good’ versus ‘evil.’”

Clinic-Bound, in Time

Although it is heady days for cancer vaccines, it is also early, researchers emphasize. Extremely few cancer patients have received cancer vaccines, and even fewer have seen significant, enduring improvement or remission of their disease.

The accelerating pace of preclinical research and surge in clinical trials, though, reflect investigators’ hope that vaccines for cancer could become as familiar, commonplace, and eventually even as effective as childhood and adult vaccines for infectious disease.

For Haglund and others living with aggressive and advanced cancers, the road ahead is uncertain. But compared to even just a decade ago, the outlook is far brighter.

“I just want to give back,” says Haglund. “I’m happy to be a part of research that will help someone else walk this path behind me.”

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, see the research profiles on vivo.weill.cornell.edu for Dr. Nasser Altorki, Dr. Niroshana Anandasabapathy, Dr. Silvia Formenti, Dr. Pashtoon Kasi, Dr. Steven Lipkin and Dr. Jedd Wolchok.