Larry Saltzman of Sacramento, California, has received two doses of a COVID-19 vaccine. What Saltzman is less sure about is how his immune system responded to his vaccination.
In 2010 at age 56, Saltzman, a family practice physician who is now executive research director at the nonprofit Leukemia & Lymphoma Society (LLS), was diagnosed with chronic lymphocytic leukemia (CLL), a cancer that starts in cells in the bone marrow. Saltzman’s version of CLL leads his bone marrow to produce cancerous B cells, a form of immune cell.
Since then, he has undergone chemotherapy, targeted therapies and radiation. In December 2019, Saltzman received an experimental CAR-T cell therapy as part of a clinical trial. Some of his own T cells were removed and modified to kill his B cells. The therapy is intended to take out cancer cells, but it also depletes healthy B cells, which are key to producing antibodies to fight infection. Saltzman wondered, would he be able to mount an immune response to the vaccine? Could he relax the social distancing protocols he’d been following?
Research has shown in recent months that the immune response to COVID-19 is different in people who have been diagnosed with blood cancer than in people without cancer and even in people with solid tumors, who generally show responses more in line with those of people without cancer. Researchers are now studying what this means for treatment and vaccination.
Understanding the Immune Response
Multiple studies have shown an elevated mortality rate for people with COVID-19 who also have cancer, but teasing apart the impacts of various treatments, cancer types and other factors on COVID-19 mortality has proven challenging.
However, one pattern that began to emerge early in the pandemic was elevated rates of severe disease and mortality for people with blood cancer. Blood cancers are, by definition, diseases of the immune system, explains Alexander Huang, a medical oncologist and researcher at the University of Pennsylvania’s Perelman School of Medicine in Philadelphia. Blood cancer itself can lead to immune dysfunction, since the cancerous cells are themselves immune cells and can crowd out and impede production of effective immune cells. The treatments used to knock back these cancerous immune cells can also impair immune function.
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Read more coverage here from Cancer Today on the various impacts of the coronavirus on people with cancer.
To better understand how the immune systems of people with cancer respond to COVID-19, Huang connected with a colleague at Memorial Sloan Kettering Cancer Center in New York City whom he had met via the Parker Institute for Cancer Immunotherapy. The researchers analyzed the clinical outcomes and immune responses of people with cancer who were hospitalized for COVID-19 at their two institutions. The results were presented at the American Association for Cancer Research (AACR) Virtual Meeting: COVID-19 and Cancer held in February 2021 and also appear in a preprint study that has not yet completed peer review and been published. (The AACR publishes Cancer Today.) They found that in a group of 100 people with cancer who were hospitalized with COVID-19 at Penn, 54% of those with blood cancer died, compared to around a third of people with solid tumors. Active cancer, prior or current smoking, and poor performance status—a measure of physical functioning—were all associated with increased mortality. However, blood cancer was still associated with increased risk of death even after the researchers adjusted for these and other factors.
The researchers also analyzed the blood of 106 people with cancer and 113 people without cancer hospitalized for COVID-19 at Penn and Memorial Sloan Kettering, counting various types of immune cells that were present and measuring antibody levels as these patients responded to their infections. While the immune responses of people with solid tumors seemed largely similar to those of people without cancer, the people with blood cancers had more unusual responses.
Most notably, blood cancer patients tended to have depleted B cells and impaired antibody responses to the coronavirus. This was not unexpected, says Huang, since some blood cancers involve the B cells and are treated with drugs that aim to wipe out these cells. In response to an infection, the B cells pump out antibodies that bind to the specific virus that is posing a threat. These antibodies circulate in the blood, binding the virus and preventing it from infecting cells, explains study co-author Santosha Vardhana, a researcher and medical oncologist who cares for people with lymphoma at Memorial Sloan Kettering. The deficits in B cells and antibody response help explain why blood cancer patients tend to do more poorly than others when they get COVID-19, according to the researchers.
However, the researchers noticed that patients with B cell deficiencies did not uniformly fare poorly when infected with COVID-19, and this is because the B cells are not the only line of defense. Producing antibodies is one key role for the immune system, says Vardhana, but antibodies can’t take care of virus that has already infected a cell. A group of immune cells called CD8 T cells patrol the body for infected cells and kill them. B cells prevent infection, says Vardhana, while “your CD8 T cells are preventing that infection from spreading by limiting the damage.”
The group with the highest mortality consisted of people who had a B cell response but lacked a T cell response, regardless of whether they had blood cancers, solid tumors or no cancer. In other words, these patients lacked the immune cells that could kill cells that had already been infected, and even a strong B cell response and copious antibodies in the blood couldn’t make up for it. Among people who had a weak but present CD8 T cell response, mortality was much higher in blood cancer patients, who were more likely to also have a lackluster B cell response. Some people with blood cancer, however, were able to compensate for their lack of B cells with a strong CD8 T cell response, and these patients had a lower rate of death than other blood cancer patients with a B cell deficiency. “One thing that our data shows is the flexibility and the power of the immune system. If your B cells are put at the way station, your T cells step up to the challenge,” Vardhana says.
People with blood cancer may also have an atypical immune response after they have recovered from acute COVID-19. Researchers at Montefiore Medical Center in New York City looked back at antibody testing results in the medical records of 261 people with cancer who had been diagnosed with COVID-19 between March and September 2020. “Our question was: Are patients with cancer able to mount immune responses to this new virus?” says hematology-oncology fellow and study co-author Astha Thakkar, who was working in inpatient oncology in the early part of the pandemic.
The researchers found that 92% of this group mounted an antibody response, according to a paper published March 22, 2021, in Nature Cancer. Zeroing in on people with blood cancer, the researcher found that 82% of people had a positive antibody test, with a lower rate of antibodies in people who had undergone stem cell transplants or treatment with targeted drugs that deplete B cells.
In the U.K., meanwhile, researchers analyzed the blood of 43 people with cancer who had been diagnosed with COVID-19—ranging from asymptomatic to severe—as part of the ongoing CAPTURE study, comparing their immune responses to those of health care workers without cancer. The participants had largely recovered from their infections by the time their blood was collected. People with solid cancer “had an effective antibody-mediated response to COVID-19,” says Samra Turajlic, a research scientist and medical oncologist at the Francis Crick Institute and the Royal Marsden NHS Foundation Trust in London who specializes in treating patients with kidney cancer and melanoma. However, some people with blood cancer lacked an antibody response or didn’t have a strong response. The people with the highest levels of T cell response were two people with lymphoma who had survived their infections while lacking an antibody response. The researchers discussed preliminary results from their study at the AACR Virtual Meeting: COVID-19 and Cancer and released the findings as a preprint.
What About Solid Tumors?
Studies indicate that immune responses to COVID-19 of people with solid tumors may be more similar to those of people without cancer.
Studies of immune signatures of people who get COVID-19 indicate that the immune responses of people with solid tumors look more like those of people without cancer than of people with blood cancer.
This does not mean that people with cancer aren’t generally at elevated risk of death from COVID-19, says Alexander Huang, a medical oncologist and researcher at the University of Pennsylvania’s Perelman School of Medicine in Philadelphia. “The reality is that the cancer patients do have a high mortality still. That has to be acknowledged that they are at high risk, probably because of many of the other factors that are contributing, because of their older age, the other comorbidities and their cancer itself,” says Huang. But, he says, it appears that people with solid tumors generally “have the right components to be able to fight the infection.” Huang is studying how people taking immune checkpoint inhibitors for melanoma respond to vaccination.
The study results may mean that this group’s risk derives more from age and coexisting health problems than from immune dysfunction related to their cancer and its treatment, says Samra Turajlic, a medical oncologist at the Francis Crick Institute and the Royal Marsden Hospital in London who specializes in treating patients with kidney cancer and melanoma.
Santosha Vardhana, a researcher and medical oncologist who cares for people with lymphoma at Memorial Sloan Kettering Cancer Center in New York City, says study results on how people with cancer respond to COVID-19 increase confidence that people with solid tumors will respond to COVID-19 vaccines and gain protection, although it is important to study this.
Risk from COVID-19 may still vary depending on solid tumor type. People with lung cancer, for instance, may be at elevated risk of severe COVID-19 and death. Early in the pandemic, some research seemed to indicate that taking immune checkpoint inhibitors—a drug commonly used to treat this group—could increase risk of severe COVID-19. Then a paper published in the August 2020 issue of Cancer Discovery indicated that after controlling for smoking, immune checkpoint inhibitors did not appear to be associated with increased risk. The factors contributing to increased risk in lung cancer remain incompletely understood, says Turajlic.
Steven Pergam, an infectious disease specialist at the Fred Hutchinson Cancer Research Center and the Seattle Cancer Care Alliance, also notes that people listed in studies as having solid tumors are a heterogeneous group, even within cancer types. Someone with colon cancer who has only received surgery for their disease might be in a very different situation than someone with colon cancer who is on aggressive chemotherapy. “The immune responses and the treatments we give to people are so varietal, it’s going to take a while to tease this all out,” he says.
When Infection Persists
Some blood cancer patients also seem to be at risk for longer-lasting infections with the coronavirus than are typical. People who are infected with the coronavirus and do not become severely ill have not been found to shed infectious virus beyond 10 days after becoming sick. Even people who become severely ill generally stop shedding infectious virus within 10 or 15 days, according to the Centers for Disease Control and Prevention (CDC), with a smaller number shedding infectious virus for up to 20 days.
A series of case studies and other small studies indicates that people with severely compromised immune systems can take longer to clear the virus. There are reports of persistent infections in people with multiple types of blood cancer, including various types of leukemia, lymphoma and multiple myeloma. These patients received cancer treatments including targeted therapies that deplete B cells, chemotherapy, CAR-T cell therapy and stem cell transplants. These persistent infections can range from asymptomatic to severe. In these studies, researchers were able to culture virus isolated from the patients up to 154 days after their initial infection.
Ji Hoon Baang, an infectious disease specialist at the University of Michigan in Ann Arbor who co-authored a case study on a patient with lymphoma whose infection persisted for at least 119 days, says that a common thread among people who become persistently infected with the coronavirus appears to be depleted B cells and problems mounting an antibody response to keep the virus from infecting cells. However, that doesn’t mean that everyone with B cell deficiencies will develop chronic COVID-19, he says, and there are not enough cases yet in the literature to definitively determine exactly who will get these chronic infections and how common they are. He adds that chronic infections with influenza—even lasting more than a year—have been seen before in people with severely compromised immune systems.
The CDC states that severely immunocompromised people may need to follow different isolation protocols than others with COVID-19, including getting additional COVID-19 testing and receiving advice from infectious disease specialists and infection control experts. Baang says that infectious disease specialists need to look at each severely immunocompromised person’s situation on a case-by-case basis, taking into account various aspects of their COVID-19 test results, treatment and cancer histories.
Baang emphasizes that the emotional toll of these persistent infections also needs to be recognized. “These patients really go through so much, not only the patients but the family members that are taking care of these patients and the doctors providing care for these patients. It’s just an emotional roller coaster in a way for everyone,” he says.
Tracing the Origins of Viral Variants
Research indicates that concerning viral variants can emerge during persistent infections in people with compromised immune systems.
At the beginning of the COVID-19 pandemic, many scientists thought the new coronavirus would not evolve in significant ways particularly quickly. The coronavirus genome is relatively large for an RNA virus, and that means it has a robust proofreading system to ensure that mistakes aren’t made as its genome is copied. However, these proofreading mechanisms can’t fix one type of mistake: deletions of pieces of the coronavirus genome. “You can’t proofread something that’s not there,” says Kevin McCarthy, a researcher who studies viral evolution at the University of Pittsburgh.
Researchers knew deletions were possible, says Paul Duprex, a virologist who directs the Center for Vaccine Research at the University of Pittsburgh. But McCarthy says he assumed at first that deletions in the region of the genome encoding the spike protein, the part of the coronavirus that latches onto cells and helps the virus enter them, would be so disruptive to the function of this protein that viruses that developed these deletions wouldn’t be particularly successful.
Then, in summer 2020, Duprex received a report that a person with multiple myeloma, who had recently received an experimental CAR-T cell therapy, had been hospitalized for a second time after being diagnosed with COVID-19. Duprex and his colleagues were able to determine by growing virus from tracheal secretions in cells in the laboratory that viable virus was still present 72 days after the man’s COVID-19 diagnosis. The man died of COVID-19.
The researchers sequenced virus present in various samples taken over the course of the man’s infection. At first the viral sequence encoding the spike protein matched that of the group of viruses circulating in Pittsburgh. However, as time passed, the sequence of the virus changed, and by day 72, there had been two potentially significant deletions in the region of the genome that encodes the spike protein.
McCarthy looked in an international database of viral sequences to see if anything similar had appeared elsewhere, finding repeatedly that the virus had developed deletions at similar locations in the gene encoding the spike protein. The results were published in the March 12, 2021, Science. In multiple cases, people with these recurrent spike mutations were also people who were immunocompromised and had developed persistent infections that had been sequenced repeatedly. These deletions seemed to have emerged independently multiple times across different geographic locations and appeared to reduce the ability of antibodies to neutralize the virus.
While the paper was being evaluated for publication, reports emerged of viral lineages, including B.1.1.7 and B.1.351, that appeared to have improved transmissibility or the ability to evade some antibodies. Along with other mutations, these variants had deletions in the same regions that had developed deletions again and again. At the same time, other researchers were publishing studies recording potentially significant viral evolution in people who were immunocompromised, including changes that seemed to arise in response to treatment with convalescent plasma, an antibody-rich treatment derived from the blood of people who have recovered from COVID-19.
“What we were seeing in this patient was actually foreshadowing what’s going on at a global scale,” McCarthy says. He emphasizes that there is no evidence that the version of the virus found in the cancer patient in Pittsburgh spread to anyone else, or even that it would have concerning properties if it did. While it did evolve in ways that changed antibody recognition, antibodies from people recovered from COVID-19 were still able to neutralize it.
There’s nothing about immunocompromised patients that makes the virus more likely to mutate during any given replication. “The rate that the virus will make a deletion or the rate that it will make a mutation—those are fixed,” says McCarthy.
However, Steven Pergam, an infectious disease specialist at the Fred Hutchinson Cancer Research Center and the Seattle Cancer Care Alliance, explains that people who are immunocompromised can have high levels of viral replication over a long period, giving the virus more chances to be copied incorrectly than in someone who is infected briefly and with lower levels of viral replication. “In your normal immune system, you’re controlling viral replication because your immune system comes in and does that work. If you don’t do that and there’s constant replication, every time the virus replicates there’s an opportunity for it to change and become more resistant or develop a new variant, and if that variant is partially attacked by the immune response and it has the ability to escape that, then you’re more likely to develop some escape mutants or variants,” Pergam says. He was involved in a 2017 study that showed that the influenza virus was able to evolve in immunocompromised people in ways that foreshadowed evolution in the global population of the influenza virus.
Ji Hoon Baang, an infectious disease specialist at the University of Michigan, notes that not all people who develop persistent infections develop concerning viral mutations. For instance, a patient with lymphoma with a persistent infection at his institution did not develop any mutations of particular concern. However, Baang does see the emergence of variants in people who are immunocompromised as a risk. “Is it the main driver behind all these variants? It’s unclear, but in my opinion, it at least is a partial driver behind how all these variants are emerging,” he says.
The researchers say that it’s imperative to protect people from developing these persistent infections in the first place. This can mean prioritizing people with compromised immune systems for vaccination, making sure their families and friends get vaccinated and generally doing everything possible to reduce the level of coronavirus infections in our communities.
“We are all collectively contributing to the appearance of variants because we are all collectively as humans getting infected with this virus. The quicker we take vaccines, the more we use masks, the more we reduce the level of replication in humanity, not just immunocompromised folks, the more likely we are to reduce the overall variant burden number,” says Duprex.
What Does Altered Immunity Mean for Vaccination?
Researchers say the high risks of COVID-19 for people with blood cancer make it all the more important for this group to receive COVID-19 vaccines. Various national organizations recommend prioritization of people with active cancer for vaccination, and cancer patients have been prioritized in some states and cities. “When you’re eligible to get vaccinated in your state guidance, get vaccinated,” says Steven Pergam, an infectious disease specialist at the Fred Hutchinson Cancer Research Center and the Seattle Cancer Care Alliance. Pergam is co-leader of the National Comprehensive Cancer Network (NCCN) COVID-19 Vaccine Committee. The committee has published and updated guidelines on vaccination for people with cancer.
The guidelines recommend that people with cancer get vaccinated as soon as they are able. The exceptions are people who have just had stem cell transplants or CAR-T cell therapy, who are advised to wait at least three months, and people who are on intensive chemotherapy for blood cancer, who are advised to wait until their levels of a type of immune cell recover. The guidelines also recommend leaving at least a few days between major surgery and vaccination.
An urgent question is how well the vaccines will work at preventing COVID-19 in various people with cancer, and particularly those with blood cancers. Vardhana says that people with depleted B cells are not expected to mount a strong antibody response following vaccination, just as this group is unlikely to mount an antibody response to infection with the coronavirus. But as with coronavirus infection, he says, the B cells are likely not the only component of the immune system that matters in vaccine response.
Vardhana says that all three authorized vaccines—the ones from Pfizer-BioNTech, Moderna, and Johnson & Johnson*—are known to induce a fairly robust T-cell response in people in the general population who are vaccinated. For people lacking B cells, “we don’t see any evidence that [vaccination] would be harmful, and if anything, we think there’s a good chance it will bolster at least your T-cell immunity,” Vardhana says. He says that a T-cell response won’t prevent people from being infected, but it could protect people from severe disease.
Pergam adds that until more data are available, it’s not possible to say if one authorized vaccine will work better for cancer patients than another. “We don’t know which one is the most effective,” says Pergam. “Until that data is available, cancer patients should get whatever vaccine comes up first.”
Researchers around the U.S. and the world are studying the immune responses of people with cancer who have received vaccines. Some initial data on the Pfizer-BioNTech vaccine in the U.K., released in a preprint in March 2021, showed that among 151 people with cancer and 54 people without cancer, the first dose of the vaccine led 97% of people without cancer to develop antibodies, compared to 39% of people with solid tumors and 13% of people with blood cancers. However, when patients were given a second vaccine dose three weeks later, as is done in the U.S., 100% of people without cancer and 95% of people with solid tumors developed an antibody response. There were not enough people with blood cancer in the study to draw conclusions about their responses to the second dose. The researchers note that the people without cancer in the study tended to be younger than the people with cancer.
Turajlic and her colleagues, meanwhile, plan to recruit a total of 1,200 people with cancer—some who already have had COVID-19 and others who haven’t—to the CAPTURE study and follow participants for two years to see if their immune responses change over time or if they develop any long-term symptoms after COVID-19. The study will also look at responses to vaccination in people with cancer. “I think the pandemic revealed very profound gaps in our knowledge in terms of the impact of cancer on immunity and infection,” Turajlic says.
Along with studying the immune responses of people with cancer to vaccination, Vardhana and his colleagues will also study what they call passive immunization. This will involve giving antibody infusions to people who did not mount an antibody response to the vaccine or who are unlikely to mount a response and seeing if this reduces their risk of infection. Vardhana and his colleagues at Memorial Sloan Kettering will also study whether they can help people with persistent COVID-19 infection to clear the virus by giving them antibodies.
For now, Pergam says, he is telling people who are immunocompromised to continue to be vigilant about avoiding infection, even after they have been vaccinated. He notes that new CDC recommendations on behavior after vaccination offer useful advice to members of the general population, but they aren’t tailored to people who may be at risk of having a less robust response to vaccination. “Remain super-cautious,” Pergam says. He adds that as COVID-19 cases in the community decline, it will become safer for people who are immunocompromised to let their guard down.
Pergam says that uncertainty about the level of protection the vaccines will offer to people who are immunocompromised means that it’s all the more essential that the family members and friends of people with cancer make sure to get vaccinated as soon as they are eligible.
The NCCN guidelines also recommend that people with cancer who have been vaccinated don’t routinely get antibody tests outside of a study. Pergam says that there is a lot of variation in the antibody tests available, and there just isn’t enough information yet to say what people should do in response to a positive or negative antibody test after vaccination. If someone does not have an antibody response to the vaccine, they might still have other types of immune responses that could be helpful, and if they do have an antibody response, it doesn’t mean they can abandon precautions.
Future studies may provide more information on what vaccination and test results mean for immunity. LLS in February launched its National Patient Registry, inviting anyone in the U.S. with a history of blood cancer to sign up to allow LLS to collect their medical records via the digital health technology company Ciitizen. Participants are also being invited to get their blood drawn at Labcorp at multiple timepoints before and after vaccination to test for antibodies to the coronavirus—including both antibodies to the spike protein, which should emerge in response to both COVID-19 vaccination and infection with the virus, and antibodies to the nucleocapsid protein, which should only be present in people who were infected with the virus. The participants will be given access to their medical records and the results of their blood tests, which they can discuss with their doctors. The medical records and blood test results will allow researchers to look for patterns in how patients with different cancers and treatment histories fare if they contract the coronavirus and how vaccination affects them.
Saltzman, who is principal investigator of the project, reports that the registry has already signed up 3,500 people, and he is one of them. More than 600 people have had their blood drawn to test for antibody responses to the vaccine. “If the CAR-T cells are still working, which I hope they are, they are eating up all my B cells,” says Saltzman. “I’m a person who has no clue whether the two doses of vaccine I’ve received have actually worked. … I want to be part of this study because I need to know. I want to know.”
*Editor’s note: On April 13, 2021, the Food and Drug Administration and Centers for Disease Control and Prevention recommended a pause on the use of the Johnson & Johnson vaccine after a small number of recipients developed a rare blood clotting disorder. On April 23, the agencies recommended that use of the vaccine resume while noting that women under 50 should be aware of the risk and that there are other COVID-19 vaccines available.
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