COVID-19 prevention must extend beyond vaccines for patients receiving cell therapies

Infection mitigation with vaccines is essential for patients with hematologic malignancies because they are at increased risk for severe infection, hospitalization and mortality if they contract COVID-19.

A meta-analysis performed early in the pandemic and published in Blood showed a pooled risk for death of 34% (95% CI, 28-39) among adults with blood cancer and a COVID-19 diagnosis. An analysis presented several months later by members of the COVID-19 and Cancer Consortium at the 2020 ASH Annual Meeting showed a 30-day mortality rate of 19% among cellular therapy recipients who developed COVID-19 within a year of treatment.

Meanwhile, COVID-19 vaccines have induced limited antibody response among patients with B-cell malignancies. This is especially true for patients who received CD19-directed chimeric antigen receptor T-cell therapies, which simultaneously attack cancer cells and healthy immune B cells.

Many patients develop B-cell aplasia after CAR T-cell infusion and will not respond well to vaccines, according to David L. Porter, MD, director of cell therapy and transplantation at University of Pennsylvania’s Abramson Cancer Center and a member of the Healio | Cell Therapy Next Peer Perspective Board.

Still, most clinicians advise patients undergoing CAR T-cell therapy to participate in the full vaccination series and follow additional post-infusion risk-reduction strategies to further mitigate infection risk.

“It's been incredibly stressful for patients receiving CAR-T,” Porter told Healio.

"There is no doubt a lot of anxiety among these patients as they wonder whether or not they will be infected with COVID-19,” he said. "Fortunately, today we have much more effective management strategies and, hopefully, the stress levels will start to come down.”

Healio spoke with cell therapy specialists about the value of COVID-19 vaccination for patients with hematologic malignancies who are being treated with CAR T-cell therapy; optimal vaccine timing for this population; whether one vaccine is more efficacious than another; and the additional steps providers should encourage patients to take to reduce their risk for the novel coronavirus.

Vaccine efficacy for CAR-T recipients

In May 2021, the Center for International Blood and Marrow Transplant Research (CIBMTR) launched a study designed to determine the safety, efficacy and durability of responses to COVID-19 vaccines among patients with hematologic malignancies who received cellular therapy.

Investigators hope to provide physicians with evidence-based recommendations about COVID-19 vaccinations for this population.

Study results are still pending, which leaves clinicians with only small, single-center analyses to inform themselves about the effectiveness of COVID-19 vaccines for patients who received CAR-T. These studies uniformly showed patients who received cellular therapies — especially those directed at CD19 — failed to generate effective levels of antibodies.

Ron Ram, MD, professor of medicine and head of the bone marrow transplant unit at Tel Aviv Sourasky Medical Center, served as an investigator on one of these studies.

Ram and colleagues found that only one of six patients who recently received CAR-T showed evidence of a humoral immune response to a third dose of the BNT162b2 mRNA COVID-19 vaccine (Pfizer, BioNTech) based on production of anti-spike antibodies. However, the investigators found evidence of a positive cellular response among five of these patients, suggesting the engagement of T lymphocytes and other immune cells.

Patients who develop B-cell aplasia after CAR T-cell therapy lack normal humoral immune reaction to vaccines and pathogens, Ram said.

“However, the cellular arm of the immune system shows significant response to the vaccine and, therefore, may also translate into vaccine efficacy against infection with COVID-19,” he told Healio.

Patients who lack humoral response to vaccines are at additional risk for severe COVID-19 infection if they are exposed to the virus, but anecdotal evidence since his group’s publication suggests the vaccines still have value because of the cellular response they elicit.

“We had four patients who were infected with the omicron variant, all of whom had B-cell aplasia with no evidence for humoral response to the vaccine, but with a decent T-cell response,” he said. “All four patients had only mild COVID-19, with a short disease course and no sequelae.”

Results of a similar small study, published as a research letter in Cancer Cell, evaluated seven patients who received CD19-directed CAR-T cell therapy. Only one showed evidence of seropositivity after two doses of a COVID-19 mRNA vaccine.

Lee Greenberger, PhD, chief scientific officer of Leukemia & Lymphoma Society and one of the coauthors of the study, said there “was no great surprise” that CAR-T recipients were unable to produce detectable levels of anti-spike antibodies in response to the vaccines, mainly because of B-cell aplasia.

“What researchers are finding is consistent: If you are treated with CD19-directed CAR-T, then you're very unlikely to make anti-spike antibodies,” he told Healio. “This is clearly not good news for patients because that is one of the mechanisms that blocks viral infection.”

Greenberger agreed with Ram that COVID-19 vaccines still likely have benefits for patients with hematologic malignancies because they promote a T-cell response.

“But, in general, our results are a warning sign that patients who receive CAR-T are at risk of getting an infection and having a poor prognosis if they get infected,” Greenberger said.

Researchers at University of Maryland conducted one of the larger single-center studies. They prospectively collected data from 18 patients with lymphoma who received CD19-directed CAR T-cell therapy. All but one patient had very poor immunoreactivity against mRNA-based COVID-19 vaccines, according to investigators.

“Patients who get CAR T-cell therapy and subsequent COVID-19 vaccines have poor antibody responses,” Saurabh Dahiya, MD, FACP, associate professor of medicine in the division of hematology and oncology at University of Maryland School of Medicine, told Healio. “[Vaccine] effectiveness in preventing infection is lower among [patients with blood cancer] compared with the overall population of patients with cancer or healthy individuals.”

Dahiya said his group’s study included only patients with lymphoma who received CD19-directed CAR-T — and no other subsequent therapies — to determine the "pure CAR-T effect" of COVID-19 vaccine immunogenicity.

Further analysis of these patients — pending publication — has shown that, despite a lack of antibody response to COVID-19 vaccines, the T-cell response they produce may provide benefits to patients who receive CAR T-cell therapy, Dahiya said. The vaccines may not prevent infection, he added, but they may provide protection against severe disease.

Optimal vaccine timing

There is near-uniform agreement in the clinical community that, despite diminished antibody formation after COVID-19 vaccines, patients who receive CAR-T should receive a full series of three vaccine doses plus a booster.

The mRNA vaccines available in the United States for COVID-19 may be more potent than the adenovirus-based product from Johnson & Johnson for patients with hematologic malignancies, Porter said. He advised that clinicians who manage patients after cellular therapy consult recommendations from the CDC, ASH and American Society for Transplantation and Cellular Therapy (ASTCT), all of which maintain websites dedicated to COVID-19 vaccination for cell therapy recipients.

“We very much recommend that patients receive COVID-19 vaccines after CAR T-cell therapy and not be dissuaded by the lack of an antibody response,” Dahiya said. “The T-cell response it does elicit may have benefits, but the degree to which it is protective against infection has yet to be established.”

Most CAR-T centers require patients to be fully vaccinated against COVID-19 before receiving therapy, Dahiya said.

“We recommend repeating the full series of COVID-19 vaccines after CAR-T because [the treatment] wipes out any immune response that may have occurred from previous vaccines,” he said.

His center’s approach to COVID-19 vaccine management for CAR T-cell recipients is based on guidance from ASH and ASTCT. Both organizations recommend starting a full series of revaccination — including three vaccine doses plus a booster — at 3 months after CAR T-cell infusion.

The CDC also has special guidance for those who have received cellular therapy during the last two years that recommends repeating the full series of vaccines plus an extra booster dose 3 months after a third dose, Dahiya said.

Ram’s center in Israel also advises vaccination at least 3 months after CAR T-cell infusion.

“However, B-cell dysfunction is still significant at this time, so sometimes we delay administration of vaccine to 6 months after CAR-T infusion,” he said.

“One dose is probably not sufficient, so repeated doses are recommended,” Ram added. “We know from our data and from other studies that immune response improves over time with repeated vaccine doses.”

Choosing a vaccine

Three COVID-19 vaccines are available in the United States. These include mRNA-based products from Pfizer and Moderna, and a vaccine from Johnson & Johnson that uses more traditional vaccine technology.

It’s likely that all COVID-19 vaccines provide some measure of protection for CAR-T recipients, Ram said.

“It is our recommendation for all eligible patients to receive any type of [mRNA] vaccine available,” he said.

Porter agreed, noting studies so far suggest similar efficacy of all available COVID-19 vaccines for CAR-T recipients. However, he emphasized information “is changing very rapidly,” and that ongoing research like the study by CIBMTR likely will help answer this question.

A head-to-head comparison between the two mRNA vaccines would be beneficial, Greenberger said, because approximately 98% of the patients is his study received one or the other.

His group’s research and data from CDC suggest antibody response may differ depending on vaccine type, with the Moderna vaccine producing significantly more anti-spike antibodies than the Pfizer product. This theoretically would make the Moderna vaccine more effective at controlling disease, Greenberger said.

“This is particularly true [for] patients with hematologic malignancies, who tend not to respond well to vaccines overall, so the differences between the vaccines get amplified,” he added.

COVID-19 prevention after CAR-T

Uncertainty about the extent to which COVID-19 vaccines protect CAR-T recipients means clinicians must encourage these patients to take additional measures to reduce risk for coronavirus transmission.

“We counsel our patients to take protective measures, such as good masking using an N95 or better,” Dahiya said.

His center also recommends patients who received CAR T cells in the past year begin treatment with tixagevimab plus cilgavimab (Evusheld, AstraZeneca), a prophylactic antibody combination approved under emergency use authorization by the FDA in December 2021 for patients at high risk of COVID-19 infection.

CAR-T recipients are eligible for the therapy because the emergency use authorization applies to individuals who have received immunosuppressive therapies. It is not intended for use as a COVID-19 treatment or to prevent infection after exposure to the disease.

Clinicians at University of Pennsylvania’s Abramson Cancer Center also recommend the antibody cocktail to CAR-T recipients, in addition to revaccination starting at 3 months to 6 months after treatment.

"Evusheld is an extremely positive advance for treatment,” Porter said.

The therapy is administered as an intramuscular injection and provides COVID-19 antibodies that last for approximately 6 months.

"When it was approved, limited supply was available,” Porter said. "Now the supply is much better and, in the last several weeks, we have been able to provide it to our entire population of patients who received CAR T cells."

Masking also must be discussed.

Porter said his center did not recommend masking after CAR-T prior the pandemic; however, staff now advises patients to continue masking in public places.

The decision ultimately rests with patients, Porter acknowledged. However, he encouraged clinicians to advise patients to consider the risks associated with various activities and monitor COVID-19 incidence in their specific regions.

"I tell patients who have just received CAR T cells and have no immunity to COVID-19 to avoid crowds and public places, maintain distancing and wear masks in public — the same type of recommendations for someone who is not vaccinated,” Porter said.

Greenberger expressed a similar sentiment.

“Given the results of our study, if a patient produces no anti-spike antibodies after vaccination, they are vulnerable,” he said. “CAR-T patients should consider taking protective measures, whether that's Evusheld or masking, or getting everybody among their family and friends to make sure that they are fully vaccinated.”

When prevention fails

COVID-19 prevention is vital for those undergoing CAR-T because of the poor disease outcomes among patients with hematologic malignancies.

Whether COVID-19 infection affects CAR-T outcomes is more uncertain, and that is one of the questions investigators involved with the ongoing CIBMTR study hope to answer.

There is no evidence to suggest that contracting a secondary infection like COVID-19 or receiving a vaccine impacts the outcomes of CAR T-cell therapy, Dahiya said.

“We have not seen any changes in outcomes with respect to efficacy when analyzing data from before and after COVID," he said.

Greenberger knows of no previous research examining the impact of COVID-19 infection on CAR-T outcomes. However, if a patient becomes infected with COVID-19 after receiving the therapy, it is unlikely to affect their functionality, he said.

“From a scientific point of view, CAR T cells will probably remain intact and keep the disease in control,” Greenberger said, noting additional study is required to confirm this.

Guidance from ASTCT reflects the uncertainty in this area.

“Though data are limited regarding the impact of COVID-19 in...cellular therapy recipients, there is concern that COVID-19 could have a significant impact on post-transplantation or post-therapy outcomes,” the organization’s Infectious Diseases Special Interest Group wrote in its guidelines for COVID-19 management among cell therapy recipients.

Becoming infected with COVID-19 does not disqualify someone from receiving CAR-T.

According to the ASTCT guidelines, CAR-T infusions should be delayed for 14 to 21 days if a symptomatic patient receives a positive a polymerase chain reaction (PCR) test. Low-risk patients can proceed to infusion if they are asymptomatic and they are negative for infection on two separate PCR tests given more than 24 hours apart. The decision to proceed with CAR-T for patients with high-risk disease who continue to test positive after the waiting period should be evaluated on a case-by-case basis.

Enduring Changes

As COVID-19 case numbers and hospitalizations decline, measures implemented to prevent infection likely will have a lasting effect on posttreatment management of patients who receive CD19-directed CAR T cells.

Prior to the pandemic, Tel Aviv Sourasky Medical Center did not advise cell therapy patients to mask in public after receiving CAR T cells. Even if the pandemic wanes, masking may be a new normal.

“We have completely changed our policy and now [masking] is strongly recommended,” Ram told Healio. “Even after loosening such recommendations for the general population, I would still advise our patients to use this precaution.”

Before the pandemic, University of Maryland’s Greenebaum Comprehensive Cancer Center staff advised CAR T-cell recipients to use a simple surgical mask after treatment. Now, clinicians counsel and encourage patients to use N95 or KN95 masks for up to a year after infusion.

“We will likely continue recommending N95 or KN95 masks for the foreseeable future,” Dahiya told Healio.

Efforts to prevent the spread of COVID-19 at the start of the pandemic — and the stress associated with it — became a shared experience around the world. Now — even as restrictions are eased in many places — they continue to apply to the most vulnerable individuals, including CAR-T recipients.

According to Dahiya, COVID-19 continues to cause significant anxiety among these immunocompromised patients. Overcoming the additional psychological burden, he added, is best accomplished by remaining on a steady course toward treatment.

“I recommend that patients move forward with potentially curative therapies like CAR-T, but after [treatment] they should strongly consider preventative strategies like vaccination, prophylactic antibody cocktails, and masking,” he said.

And for CAR-T patients who develop COVID-19, Dahiya said newly approved antiviral medications — such as nirmatrelvir (Paxlovid, Pfizer) — should help ease patients’ angst while helping prevent serious disease or death.

“We have learned that the types of patients who are eligible for CAR-T are at higher risk for negative COVID-19 outcomes and that stress can be unimaginable for someone not in this situation,” Porter said. “It's not just about limiting exposures that a patient can control — such as going out in public or eating at restaurants — but includes exposure to those like your family and friends.”

Because many CAR-T recipients will lack immunity to COVID-19, these patients and their health care providers must maintain added vigilance while the world is opening up around them, he added.

Cell therapy recipients have always been and will remain susceptible to several different infections that require them to take special precautions compared with individuals who have normal immune systems, Porter said.

“However, I don't think patients are going to have to stay indoors, wipe their groceries down and wear a mask everywhere — they will be able to go to restaurants and travel if they take good, common-sense precautions,” he said. “Moving forward, as the incidence of COVID-19 goes down and our preventive and treatment strategies get better, patients will be freer to resume a more normal life.”

References

Dahiya S, et al. Blood Adv. 2022;doi:10.1182/bloodadvances.2021006112.
Greenberger LM, et al. Cancer Cell. 2021;doi:10.1016/j.ccell.2021.07.012.
Ram R, et al. Transplant Cell Ther. 2022;doi:10.1016/j.jtct.2022.02.012.
Rubenstien S, et al. Abstract 1632. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
Vijenthira A, et al. Blood. 2020;doi:10.1182/blood.2020008824.
Waghmare A, et al. Biol Blood Marrow Transplant. 2022;doi:10.1016/j.bbmt.2020.07.027.

For more information:

Saurabh Dahiya, MD, FACP, can be reached at sdahiya@umm.edu.

Lee Greenberger, PhD, can be reached at lee.greenberger@lls.org.

David L. Porter, MD, can be reached at david.porter@uphs.upenn.edu.

Ron Ram, MD, can be reached at ronr@tlvmc.gov.il.