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Michele Nadeem-Baker is steeling herself for another winter. Diagnosed with chronic lymphocytic leukemia in 2012, she lives with an impaired immune system that even a third dose of Moderna’s Covid-19 vaccine may not be able to rouse. Living in Boston in November now that the weather has turned cold means an end to backyard dinners and a return to a world narrowed by fear of infection.

“I am not alone in that feeling,” said Nadeem-Baker, a patient advocate who also spoke to STAT in June. “Everyone is dreading yet another winter in lockdown. Just because there are these third vaccinations, it doesn’t mean everyone is protected. There is still a part of the population that is not.”

It’s another reminder, like this past summer’s soon-deflated vaccine euphoria, that people whose immunity is compromised by cancer, organ transplantation, or autoimmune diseases — and their treatments — cannot afford to let their guard down. Nadeem-Baker says people in her patient groups have their eyes on monoclonal antibody treatments, the infusions that can give cancer patients the coronavirus-fighting antibodies their own bodies can’t make.

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The combination treatments, authorized by the Food and Drug Administration and made by Regeneron and Eli Lilly, have already kept Covid patients in general from developing more severe illness, if they are treated early in their infections. Administered intravenously in a one-time, roughly hour-long process, each treatment costs about $1,250 per dose under deals the drug makers have struck with the federal government. It’s too soon to say what the Omicron variant’s impact could be on the effectiveness of the monoclonal antibodies.

As daylight fades after 4 p.m. in northern latitudes, some patients see glimmers of hope in these treatments while they wait for a better read on what protection even impaired immune systems might muster from third and fourth vaccine doses.

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Cancer hospitals across the U.S. — including Dana-Farber Cancer Institute in Boston, Memorial Sloan Kettering Cancer Center in New York, and MD Anderson Cancer Center in Houston — are giving the therapies to some patients before they get sick but after they’ve had close contact with someone who has tested positive for Covid.

“We are currently using monoclonal antibodies to treat certain patients who are at risk for severe disease who are infected with Covid, and we’re also using monoclonal antibody prophylaxis for patients at high risk for severe disease who have had a significant exposure,” said Meghan Baker, an infectious diseases physician and hospital epidemiologist who works with immunocompromised patients at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston. “This is in an individual who is not expected to mount an optimal response to the vaccine.”

Cancer patients are less likely than other people to enjoy the remarkable protection provided by the rapidly developed Covid vaccines. The death of Colin Powell, who died from complications of Covid in October and also had multiple myeloma, underscored the fact that even people with cancer who are fully vaccinated are at much higher risk of infection than people who can muster a robust immune response to vaccination. A study published last week in JAMA Network Open found that patients with multiple myeloma were at higher risk of breakthrough infections than people without cancer, and that those breakthrough infections were more likely to lead to hospitalization.

For people who are immunocompromised, like cancer patients, the standard Covid-19 vaccine regimen may offer little to no protection. Alex Hogan/STAT

There are two reasons why. Blood cancers attack the immune system, and so do treatments. Leukemia, lymphoma, and multiple myeloma arise in cells that create antibody-producing cells, so drugs that attack the cancer remove not just malignant cells, but also benign immune cells. Bone marrow transplants wipe out a person’s entire immune system, whose rebuilding takes months. That means a person has to start over with all vaccinations — not just against Covid — to teach those new immune cells to fight the invading coronavirus, flu, or other pathogen.

Tobias Hohl, chief of infectious diseases service at Memorial Sloan Kettering, sees monoclonals as potentially something more than a treatment to ward off severe illness or act like a post-exposure shield: He envisions a bridge to better vaccine-driven immunity.

Because there is no on-off switch for being immunocompromised, it’s more like a transient state for cancer patients, depending on the type of cancer they have and where they are on their treatment journey. That’s where monoclonal antibody treatments might come in, Hohl said. If someone was starting chemotherapy likely to damage their infection-fighting immune cells, they would be vulnerable to any kind of infection for three to six months. Monoclonal antibodies might temporarily protect that patient until immune function is regained. Regeneron says its trials showed its drug worked for two to eight months.

“We are specifically concerned about patients in which a cancer or the therapy for the cancer impacts their ability to form antibodies or protective T cells,” he said. “For very vulnerable patients at times of high community attack rate, we could bridge them with monoclonal antibodies until it is safe to either resume or renew vaccination because they can now respond to vaccines.”

Those patients may have had a less-than-robust response to Covid vaccination — even after a third dose, which the FDA authorized in August for immunocompromised people — because cancer has so severely injured their immune system. That weakness is generating interest now in monoclonal antibodies as an immune-reconstitution therapy. “I think that is going to be something that we’re going to see more and more: trying to bridge that time-dependent period in terms of the immune injury,” Hohl said. “That’s the strategy that we are going to roll out.”

Monoclonals are here, while antiviral pills developed by Pfizer and Merck with its partner Ridgeback Biotherapeutics are still awaiting FDA authorization. They may not be ideal for a cancer patient whose treatment could be impacted by potential side effects from one of the two drugs, Pfizer’s Paxlovid. A protease inhibitor familiar to people who know that class of drugs from its success taming HIV, the oral treatment would interact with cancer-fighting therapies, Hohl said. Side effects could also be troubling. Merck’s pill, called molnupiravir, works in a different way to interfere with the process the coronavirus uses to reproduce itself, with uncertain implications for cancer patients or other people whose immunity is impaired. So far the only data from trials of the pills have come from the companies, not peer-reviewed journals, so it’s too soon to gauge their impact for cancer patients.

That leaves vaccination as the preferred method of protection, but one whose strength or weakness has been challenging to measure for cancer patients.

“We know they’re not going to be the best candidates for the vaccine, but a little bit of immune response to the vaccine may impact their outcomes” if they get Covid, said Roy Chemaly, chief infection control officer at MD Anderson Cancer Center. Patients there may be offered monoclonal antibodies after exposure to someone who’s tested positive for Covid if the patient is at high risk for severe Covid, not fully vaccinated, and not expected to mount an adequate response to vaccination. “This gets you to the question of durable antibodies, and also at what level they may provide protection. No one knows, really. It’s all a surrogate marker of protection.”

Hohl called antibody tests outside of research labs that simply count antibodies — like leaves floating in a river — an imperfect measure of immunity because they don’t distinguish between antibodies that neutralize the virus and those that don’t. Looking for T cells — like a certain type of fish swimming in a river — to measure another kind of immune response is also more complicated. “We don’t have a way to fully assess in a quantitative way, if you’re above this level, you’re protected, or if you’re below this level, you’re not.”

As the months go by and more immunocompromised people have received third doses — and the Centers for Disease Control and Prevention recommends patients talk with their doctors about fourth doses — a picture of better-than-nothing responses is emerging. Looking just at cancer patients, a Nature Cancer study published in October found that patients with blood cancers were more likely than other patients to have no detectable neutralizing antibodies against the original coronavirus strain or its variants of concern. A Cancer Cell paper posted this month had more encouraging results: Among cancer patients who had no signs of antibodies after two doses, 56% of them did develop antiviral antibodies after a third vaccine dose. A small study from Israel published last week in JAMA Oncology also suggested a “generally positive and immediate antibody response” to third Pfizer doses given while patients were receiving chemotherapy.

Without agreement on what the antibody or T cell targets should be, patients and their doctors fall back on tried-and-true strategies such as vaccination and additional doses for cancer patients combined with masking and vaccination for people who surround them, with an eye toward regional levels of cases.

“We do recommend that patients who are immunocompromised do maintain precautions in their day-to-day lives,” Dana-Farber’s Baker said. “That does include masking, whether outside of the home, staying away from crowds, staying in well-ventilated areas, hand hygiene, and also encouraging those around them to get vaccinated.”

Meanwhile, people in colder climes, like Nadeem-Baker, wait for spring.

“There is a little hope on the horizon, but I mean, how long will it take?” she asked. “We’ve been like this for so long.”

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