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Prior treatment with cancer drug likely renders COVID-19 vaccine ineffective, study finds

Rituximab, a drug widely used in patients with lymphoma, blunts or eliminates the antibody response to COVID-19 vaccines if it is administered before them, Stanford researchers say.

- By Krista Conger

The mRNA vaccines for COVID-19, when given to patients less than a year after treatment with the cancer drug rituximab, produced little or no antibody response, a study found.
Nigel Walker

People who have been treated with rituximab, a widely used cancer drug, or similar drugs respond poorly or not at all to subsequent COVID-19 mRNA vaccines, according to a study by researchers at Stanford Medicine.

In contrast, vaccination immediately prior to such treatments can generate a months-long, durable antibody response, the study found.

Rituximab, marketed under the brand name Rituxan, is widely used alone or in combination with other treatments in people with lymphomas, a type of blood cancer; last year, around 90,000 people were diagnosed with the disease in the United States. The drug targets a molecule called CD-20 found on the surface of immune cells called B cells.

The researchers did not directly assess whether patients treated with rituximab — or with other drugs targeting CD-20 — before being vaccinated subsequently had higher rates of infection with the virus that causes COVID-19. But the findings strongly suggest that people who are newly diagnosed with lymphoma should be offered the vaccine prior to beginning rituximab or similar drugs.

“This finding is likely to be practice-changing,” said Ronald Levy, MD, professor of oncology. “We found that antibody responses to the COVID-19 vaccine were blunted in people who received rituximab up to a year before vaccination. But if they were vaccinated prior to treatment, most responded and were able to hold on to that response during their rituximab treatment.”

Levy is the senior author of the study, which was published Jan. 6 in Blood Cancer Discovery. Oncology instructor Tanaya Shree, MD, PhD, is the lead author.

Measuring antibodies

The researchers measured the vaccination response in 126 lymphoma patients who had been treated with rituximab by assessing the levels of antibodies in their blood to the virus that causes COVID-19. Measuring antibodies in the days and weeks after vaccination is a common method that has been used throughout the pandemic to assess a vaccine’s effectiveness. A strong antibody response to a vaccine is taken to mean the immune system is responding appropriately.

Ronald Levy

Levy and his colleagues found that, overall, 55% of the 126 patients developed antibodies that could block the virus’s spike protein from binding to its receptor in a laboratory dish. But none of the 31 patients who received rituximab six or fewer months before being vaccinated generated any blocking antibodies. The time elapsed since a patient’s last rituximab treatment — a span that varied between mere days and 18 years — was a significant predictor of vaccine response. The researchers found that people who had received rituximab treatment 12 or fewer months before being vaccinated were less likely to mount an antibody-mediated immune response to the vaccine.

It makes sense that rituximab would affect antibody production. The drug, developed in collaboration with Levy’s team in the early 1980s, binds to a molecule called CD-20 on the surface of B cells — a specialized type of immune cell that makes antibodies to combat pathogens. Lymphomas are cancers that occur when B cells begin dividing uncontrollably, and rituximab seeks out and kills these cells in lymphoma patients.

“When we compared the effects of chemotherapy or other drugs, we found that it was mainly recent rituximab treatment that limited a person’s response to the vaccines,” Levy said.

Additional antibodies have recently been developed against CD-20, and the researchers predict they would also likely interfere with the COVID mRNA vaccines.

Lingering antibodies

Fifteen of the 126 patients had been fully vaccinated against COVID-19 prior to starting rituximab treatment, most just a few weeks before. Ten of these patients generated a blocking antibody response to the virus. In six of them, that response persisted at least four months after they started rituximab treatment.

The researchers don’t know how much time needs to pass between vaccination and rituximab treatment for the vaccine to be effective. However, one patient who began cancer treatment between the first and second doses of vaccine did make antibodies that lasted throughout their cancer treatment.

The results also call into question the practice of using rituximab as a maintenance therapy for people whose lymphoma has been successfully treated.

“It’s so important to give people the chance to mount an effective immune response to vaccinations, particularly now,” Levy said. “There has been controversy in the field about the value of continuing rituximab treatment after the initial therapy because doing so has not been shown to help these patients live longer. Our study suggests this practice of extended treatment should probably be abandoned in the COVID era.”

The research was supported by the National Institutes of Health (grants R35CA19735306 and K08CA252637), the Leukemia and Lymphoma Society, Fast Grants, and the Stanford Chem-H Innovative Medicines Accelerator program.

Stanford Medicine integrates research, medical education and health care at its three institutions - Stanford University School of Medicine, Stanford Health Care (formerly Stanford Hospital & Clinics), and Lucile Packard Children's Hospital Stanford. For more information, please visit the Office of Communication & Public Affairs site at http://mednews.stanford.edu.

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