From its earliest days as a novel virus in Wuhan, China, the COVID-19 pandemic has always been a particular threat to cancer patients. Cancer itself taxes the patient’s immune system. When surgery alone cannot eliminate the cancer, treatments like chemotherapy, radiation, transplantation and newer targeted therapies exact a greater toll. Without the defenses of a healthy immune system, the common cold becomes a threat — and a novel coronavirus potentially deadly.

COVID vaccines became available under emergency use authorization in December 2020, and frontline medical staff were first to receive the protective jab. Cancer patients and others with compromised immune systems weren’t far behind.  Since then, they’ve been among the first cleared to receive second doses and boosters.

But 18 months later, questions remain. How much protection do the vaccines offer our patients — and for how long? Do they offer equal protection for all regardless of the type of cancer? The answers are vital for patients, caregivers and families struggling to strike a balance between minimizing risks and living their lives.

Thankfully, Moffitt Cancer Center has the facilities and personnel needed to find some of those answers, including a world-renowned epidemiologist best known for her work to prevent and eliminate cancers caused by the human papillomavirus through use of the HPV vaccine.

Surveying Community Risk

Anna Giuliano, Ph.D., is the founding director of Moffitt’s Center for Immunization and Infection Research in Cancer (CIIRC). She was instrumental in turning the cancer center’s research attention to the pandemic’s potential impact on our patients, initiating a surveillance study in the fall of 2020 before COVID vaccines were available to the public.

“The first study we did was to understand what was happening in our community,” said Giuliano. “We know that what happens in the community strongly influences what happens with our cancer patients.” Fifty-thousand Hillsborough County residents were contacted at random by letter, postcard or email to see if they would be willing to answer a questionnaire and come to a Moffitt clinic to contribute a blood sample for the study. Nearly 900 agreed.

To examine those samples, CIIRC co-director Shari Pilon-Thomas, Ph.D., first had to develop a testing mechanism, or assay, to measure COVID antibodies in the blood. “While my lab had the experience needed to develop the assays, we faced several challenges including finding and generating the reagents needed to develop the new assays at a time when many of Moffitt’s research facilities were shut down due to COVID,” noted Pilon-Thomas. Fellow Moffitt researcher Ernst Schonbrunn, Ph.D., contributed a protein critical to creating the new assay. Then, while continuing their other research efforts, team members in the Pilon-Thomas and Giuliano laboratories went to work testing nearly 900 blood samples.

The results showed roughly 20% already had traces of COVID antibodies in their blood, evidence of a past COVID infection. That’s twice the prevalence of confirmed COVID infections reported by state health agencies at the time — a significant risk for the county’s immunocompromised citizens.

Vaccines Cause Quick Research Pivot

Before the surveillance study was even completed, the first COVID vaccines were being distributed to frontline health care workers nationwide. In January 2021, Gov. Ron DeSantis ensured Moffitt Cancer Center was among the first to receive thousands of doses of vaccine — a boon to our staff and an opportunity for our patients.

“With that amount of vaccine availability, (Moffitt President and CEO) Dr. Patrick Hwu and (Moffitt Chief Medical Officer) Dr. Bob Keenan decided that we also needed to start vaccinating our cancer patients,” recalled Giuliano. “But at that point, we had no idea how they would respond to vaccine — who would respond well and who wouldn’t. There was nothing available in the literature.”

Giuliano saw an opportunity to change that with a study that would capture Moffitt patients’ data before and after they received the vaccine. But setting up this type of research study can often take months, and our patients needed any protection the vaccines might afford as soon as possible.

“With Dr. Hwu’s support, we were able to get the Moffitt machinery working as fast as I think it has ever worked in getting contracts, institutional research board approvals and all the procedures in place,” said Giuliano.

Moffitt had an advantage in making things happen quickly, an ongoing research protocol called Total Cancer Care® (TCC).  Developed at Moffitt in the early 2000s, TCC has been enrolling cancer patients nationwide to share blood and tissue samples, as well as medical information over the course of their lifetimes. The data are used to help researchers and physicians improve cancer prevention, detection and treatment.

As patients came through Moffitt vaccination clinics in mid-January of 2021, those who had already consented to be part of the TCC protocol were asked to provide a blood sample before their first dose of vaccine, as well as periodically post-vaccination — potentially for as long as two years — to track the level of COVID antibodies over time. In total, 515 patients with a variety of cancer diagnoses agreed and qualified to be part of the study.

Getting those patients enrolled was the easy part, said study co-investigator Jeffrey Lancet, M.D., a blood cancer specialist and researcher who chairs Moffitt’s Department of Malignant Hematology. “Our diverse patient population is very well educated in their disease and risks. People were literally knocking down the doors trying to find a way to get this potentially lifesaving vaccine.”

The trickier part was designing the research protocol to capture information about the many variables in such a diverse group of cancer patients. “We went into this thinking that the vaccine may have very different effects on patients based on the type of cancer they had, the extent of that cancer, the treatment that they’re receiving, the time that they’d been receiving treatment and many other factors that could play into it,” said Lancet. “We were very careful about identifying all the variables that could impact the efficacy of a vaccine so that we’d be better able to understand, in the end, which patients are most likely to benefit and those least likely to benefit.”

In particular, Lancet wanted to be sure this study would address a question critical to the blood cancer patients he treats. How does their particular diagnosis — lymphoid or myeloid cancer — affect response to the COVID vaccine?

It’s already established that patients with lymphoid or B-cell diseases in particular are less likely to mount a response to vaccines. “That’s no surprise because you need B cells to make antibodies,” said Lancet. “And if you’re suppressing your B cells, either through the disease process itself or through treatments, chances are you’re not going to make antibodies. But we didn’t know if that would be the case with myeloid cancer patients. We also knew that patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) had high rates of morbidity and mortality once infected with COVID. So, the logical question to ask was does the vaccine do anything to protect these patients?”

To get some answers, the study ensured a significant number of patients with MDS and AML would be enrolled. The data would become part of a separate research abstract on this patient population, which was presented at the American Society of Hematology conference in December 2021.

Preliminary Results Show Promise, Pitfalls

By the summer of 2021, the preliminary data were already beginning to show the differing vaccine responses. Overall, most participants (over 70%) produced some level of antibodies after the first vaccine. Even more (90%) did so after a second dose.

But the level of antibodies in their blood couldn’t match the amount produced by healthy adults. Only those cancer patients whose pre-vaccination blood samples contained COVID antibodies (presumably from an earlier infection) responded to the two-dose vaccine regimen with nearly as robust antibody levels as healthy controls. And in all cases — healthy or immune-compromised — antibody levels peaked within weeks after vaccination, then declined over time.

"Our diverse patient population is very well educated in their disease and risks. People were literally knocking down the doors trying to find a way to get this potentially lifesaving vaccine."

- Dr. Jeffrey Lancet, Malignant Hematology Department

Patients with solid tumors were more likely to develop antibodies after two shots than those with blood cancers. The rates were lower for those with lymphoid blood cancers, particularly among patients with B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia who were on active treatment. The majority of study participants with myeloid blood cancers were positive for antibodies after their second vaccination. However, most of these patients were in remission or on lower intensity therapy at the time of vaccination. Further study will be required to see if those undergoing more aggressive treatment respond as well.

Types of treatment and their timing relative to vaccination also seem to matter. Patients taking anti-CD20 medications like Rituximab that are used to deplete B cells showed no antibody response to the vaccines. Other treatments like BTK inhibitors or CD19 CAR T therapies reduced the vaccine response.

To Giuliano, the greatest concern was that even after two doses of vaccine, few if any of the study participants had produced as much antibody as healthy adults. And even the healthy adults’ antibody levels weren’t enough to stave off breakthrough infections with a then-emerging variant called omicron.

More Variables Mean More Research

When booster shots were approved in September of 2021 for those over 65 or immunocompromised, Giuliano knew there wouldn’t be time to develop another research trial focused on third-dose response. She could see that participants in Moffitt’s ongoing study were already showing declining antibody levels. They needed a third dose, and their responses would have to be tracked in another observational study. This additional third dose study would also give Lancet an opportunity to track some outliers who hadn’t developed antibodies after two shots — but did respond after three.

The list of variables to take into account for each research study continues to grow: boosters, new variants like omicron, past COVID infections and even the use of new therapeutics like monoclonal antibodies to prevent or treat COVID infections. Lancet offered just one example: “What is the importance of future vaccinations in people who were infected with the omicron variant? You could probably bring together a thousand researchers and assign each of them a different variable to study and you’d have hundreds of highly publishable papers in the end.”

“One of the frustrations in working with coronavirus research is that every month, something dramatically changes,” noted Giuliano. “It’s very hard to keep up with that and move the research machinery to be able to respond.”

Amid the uncertainties of the COVID era, Lancet said one thing seems certain. “This is not going away. We need to devote more resources to its study, but we can’t do that by simply extending everyone’s bandwidth at the expense of other duties. People are still getting cancer and needing treatment from us.” He said it’s entirely possible cancer centers will need to create specific positions devoted solely to developing COVID protocols and vaccine strategies for patients.

Giuliano remained hopeful that evolution theory will play out. “Viruses evolve. They’re just like humans, they want to propagate. The best way to do that is to actually cause some disease (sneezing, coughing) that helps to spread the virus. But it doesn’t really pay to kill the patients. So, if you look at viral evolution, the pattern is to become less and less disease-promoting and more and more transmissible, like omicron.”

In the meantime, Moffitt will continue to research vital information for both patients and providers to guide their decision-making. Giuliano noted that the studies to date have drawn together more than 100 Moffitt team members from phlebotomists drawing blood samples and vaccinators in clinics, to research staff who developed testing assays and those in the Immune Monitoring Core who continue to use them processing samples.

“It felt like we were all working with the same mission in mind,” said Giuliano. “And I can tell you when people believe in something, it’s amazing what can happen.”