November 09, 2020
Predicting and preventing CAR T cell therapy side effects in lymphoma patients
BY Devon Carter
CAR T cell therapy has changed the way aggressive B-cell lymphoma is treated. Previously, when patients had a second recurrence after receiving chemotherapy, or when they stopped responding to treatment, there were few next steps to manage the disease. But now, CAR T cell therapy is offering those patients a new option and more time.
There are three CAR T cell drugs approved by the Food and Drug Administration (FDA): Yescarta, Kymriah and, most recently, Tecartus. They’re used to treat relapsed or refractory diffuse large B-cell lymphoma, follicular lymphoma, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and mantle cell lymphoma.
“CAR T cell therapy is very effective,” says Paolo Strati, M.D. “A study showed that patients who relapsed after chemotherapy had a 10% chance of survival at five years, but Yescarta has driven that survival rate up to 45%.”
Although CAR T cell therapy has been a breakthrough treatment, not every patient has the same results. Working along with Sattva Neelapu, M.D., and Michael Green, Ph.D., to improve CAR T cell therapy, Strati aims to understand the biology behind the side effects so that they can be better managed and longer remissions can be achieved.
Neurotoxicity and cytopenia are leading CAR T cell therapy side effects
With CAR T cell therapy, patients avoid common chemotherapy-related side effects like nausea, vomiting and hair loss. But many still experience side effects that are unique to the cellular therapy. There are three common side effects.
First, patients may experience cytokine release syndrome (CRS), an inflammatory reaction that results in fever, low blood pressure and low oxygen levels. Although 10% of patients experience severe CRS, it can be managed with a biologic drug called tocilizumab that targets Interleukin-6 (IL-6).
Second, many patients may experience neurotoxicity. They can get confused, have seizures or go into a coma. In an MD Anderson study of 100 large B-cell lymphoma patients who received Yescarta, more than 60% of patients experienced neurotoxicity and in more than 40% of those patients, it was severe.
Lastly, MD Anderson research has shown more than 30% of patients have prolonged myelosuppression. This results in low blood counts, known as cytopenia. Although blood transfusions can help raise blood counts, cytopenia puts patients at greater risk of infection.
“Neurotoxicity and cytopenia are frequent complications of commercially available CAR T products, but we still don't know much about them,” Strati says. “Our goal is to understand what drives these side effects to better predict – and hopefully prevent – them.”
Avoiding neurotoxicity, extending remission for lymphoma patients
A study led by Green examined the remnants of CAR T cell product in infusion bags after a patient received the therapy. A higher number of monocyte-like cells in the CAR T cell product was linked to patients who later developed neurotoxicity. “These results suggest that these cells may be responsible for neurotoxicity,” Strati says. “So we’re hopeful that they can be used as a predictive tool.”
In addition to the risks associated directly with neurotoxicity, MD Anderson research has found that patients who experience neurotoxicity also tended to have a shorter survival. “This is surprising because neurotoxicity is a surrogate marker of the CAR T cells being active,” Strati says. Studies have found that CRS is a sign of CAR T cell proliferation, so why are patients who have neurotoxicity doing worse?
Strati’s research suggests that it’s associated with corticosteroids, which are used to manage neurotoxicity. “Corticosteriods can affect the CAR T cells’ ability to proliferate and work properly,” Strati says. Using steroids early or for a long time has been linked to early disease progression. “We need corticosteroids-sparing strategies, and we’re hoping we’ve done just that,” Strati says.
Green’s study found the monocytes in the CAR T cell product produce Interleukin-1 (IL-1), which can be targeted by an existing drug used in arthritis called anakinra. “At MD Anderson, we published our experience of off-label usage of anakinra and demonstrated that it’s safe and effective for mitigating neurotoxicity in these patients,” Strati says.
He has opened a clinical trial to investigate whether this approach offer longer remissions for more patients who receive CAR T cell therapy. “We’re not just trying to treat the neurotoxicity,” Strati says. “We’re working to prevent it and extend lives.”
New approaches to predicting and managing cytopenia after CAR T cell therapy
Cytopenia presents challenges in patients who’ve received CAR T cell therapy. MD Anderson research has shown that even two years after receiving CAR T cell therapy, 20% of patients don’t have fully functioning immune systems. Strati cites an MD Anderson study that found patients who’d had a previous hepatitis B or C infection had the virus reactivated after they stopped maintenance antibiotic treatments required after CAR T cell therapy.
But, Strati says, there’s hope for predicting which patients may endure this long-term side effect. A study found that patients with persistent or prolonged cytopenia produce more cytokines and chemokines from monocytes and macrophages that tends to peak seven days after the CAR T infusion.
“We now have the target of these monocytes and macrophages, just like with neurotoxicity, as well as a specific timeframe to develop approaches to prevent this lingering side effect,” Strati says. He’s now prospectively collecting bone marrow samples as well as peripheral blood from patients, and, along with Neelapu and Green, performing single-cell RNA sequencing to further understand the biological mechanisms driving cytopenia. “We hope it leads to an investigator-initiated study of novel agents to relieve cytopenia in these patients,” Strati says.
“I’ve been in the field for some time now, and the change I’ve seen over the last few years is unlike ever before,” he adds. “I feel fortunate to work at MD Anderson because this is where most of the innovations in lymphoma have started.”
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Our goal is to understand what drives these side effects to better predict – and hopefully prevent – them.
Paolo Strati, M.D.