When they work, engineered immune cells called CAR T cells can beat back even advanced leukemias and lymphomas.

But there is a catch. The proteins they sniff out on cancerous cells can also appear on healthy B cells, which make infection-fighting antibodies. The CAR T cells can’t distinguish between friend and foe, so they destroy both.

That collateral damage may leave patients vulnerable to infection. No B cells means no protective antibodies — tiny Y-shaped proteins that neutralize bacteria and viruses.

The long-term effects of CAR T-cell therapy on this key part of the immune system are poorly understood, said Joshua Hill, MD, an infectious diseases specialist at Fred Hutchinson Cancer Research Center. And no data exist to guide efforts at preventing infections in these high-risk patients.

Hill plans to change that. He will use a new five-year, $3.3 million grant from the National Cancer Institute’s Cancer Moonshot program to study the holes this immunotherapy leaves in patients’ defenses against infection — and how doctors can fill them. Hill will lead an interdisciplinary team of researchers from Fred Hutch and Seattle Children’s focused on CAR T-cell therapies used to treat blood cancers.

As the number of patients treated with CAR T cells grows, the work will address critical knowledge gaps in how best to provide long-term care, Hill said.

“(CAR T-cell therapy) is a new frontier with unique infection risks because we’re knocking out B cells,” he said. “The goal of this work is to understand what exactly is happening to the immune system and what are the most cost-effective and patient-friendly ways of dealing with it.”

The ghosts of infections past

Chickenpox may be a dim childhood memory, and your first brush with flu likely happened too far back to recall.

But your blood remembers.

Traces of nearly every virus your immune system has encountered still circulate in the form of antibodies. When a virus invades, “naive” B cells become active. They start to produce antibodies that attack the virus. These cells can ultimately become long-lived plasma cells, which remember past infections and churn out antibodies to foil reinvading viruses.

But for patients who undergo CAR T-cell therapy, are there any plasma cells left to remember — and respond to — those old foes? And can they defend against new threats?

To start to answer those questions, Hill will turn to a novel tool called VirScan. This test can take a comprehensive “snapshot” of a patient’s immunity by detecting antibodies to hundreds of viruses. Hill plans to collect and test blood samples from over 100 children and adults prior to treatment and at six-month intervals afterwards. That serial look will help determine how the CAR T cells affect patients’ immune responses to specific pathogens. 

Hill also wants to understand how these patients might respond to vaccination. Vaccines could be an alternative to the most common way doctors try to curb infection risk: monthly injections of antibodies. But this immunoglobulin (IVIG) therapy is expensive and can cause side effects, Hill said. And last year, the FDA reported a shortage of IVIG products in the U.S.

Perhaps most importantly, no one knows if this is a viable long-term solution, Hill said. “We are treating children with CAR T cells. Is giving them monthly shots for the rest of their lives the best strategy to protect them from infections?”

Hill hopes vaccines could provide a cheaper, more convenient strategy. He will use the collected samples to study how CAR T-cell treatment affects patients’ pre-existing immunity to vaccine-preventable infections. And in the third part of his new project, Hill’s team will study how patients’ immune systems respond to vaccinations for infections like the flu, hepatitis and measles to evaluate whether patients can generate normal vaccine responses after CAR T-cell therapy.

Hill is eager to further explore how CAR T-cell therapies used to treat blood cancers might impact patients’ infection risk. In November, he published a paper showing that adults who received a certain type of CAR T-cell therapy maintained their existing immunity to measles. That therapy targeted a protein that appears on most B cells but is absent on long-lived plasma cells.

The finding suggested that plasma cells aren’t direct targets of some CAR T cells and can continue to provide long-term protection against infections. The new grant will let him build on that research to include pediatric patients as well as another type of CAR T-cell therapy targeting a different protein that does appear on plasma cells.

“Now that more patients are responding to CAR T-cell therapy, we need to understand how to care for them over the long haul,” Hill said. “We hope this research will guide evidence-based strategies for infection prevention, such as vaccination or IVIG therapy, to improve outcomes in this rapidly growing population of high-risk individuals.”

This article was originally published on January 17, 2020, by Hutch News. It is republished with permission.