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Clinicians Devise Guidelines for Handling CAR T-Cell Side Effects
Immune-cell–based therapies opening a new frontier for cancer treatment carry unique, potentially lethal side effects that provide a new challenge for oncologists. A team led by clinicians at The University of Texas MD Anderson Cancer Center is addressing that issue by proposing guidelines for systematically dealing with the toxicities of the drugs.
Their work, published in Nature Reviews Clinical Oncology, confronts the two main side effects of chimeric antigen receptor (CAR) T cells, white blood cells genetically engineered to strike cells with a specific target on their surface.
“CAR T cells provide an entirely new level of improved disease response among patients with certain blood cancers and hold promise for more wide-ranging use,” said Elizabeth Shpall, MD, deputy chair and professor of stem cell transplantation and cellular therapy at MD Anderson. “The algorithms that we published are conservative, detailed, and will help us save lives as we move forward with these exciting but also more toxic therapies.”
The review covers a variety of research on CAR T therapies by many institutions and includes insights based on more than 100 patients treated at MD Anderson, Moffitt Cancer Center in Tampa, Sylvester Cancer Center at the University of Miami, and Mayo Clinic Cancer Center in Rochester, Minnesota. Patients were treated by the coauthors with CAR T cells under development by four companies for leukemias and lymphomas that attack white blood cells called B cells. They target CD19, a protein found on the surface of both malignant and normal B cells.
In clinical trials of CAR T for patients who have had all other treatments fail, response rates range from 50% to 90%. But two side effects have emerged during clinical trials that were previously uncommon to cancer treatments:
- Cytokine release syndrome (CRS), also known as cytokine storm, an escalated immune response that causes flu-like symptoms and can be fatal.
- Neurological toxicity that the researchers have named CAR-T-cell–related encephalopathy syndrome (CRES), which can sometimes lead to lethal swelling in the brain.
Both CRS and CRES are treatable, with early identification important to swift improvement. The review provides specific recommendations for pretreatment preparation, monitoring of patients during and after CAR T infusion, identifying and staging emerging CRS and CRES, and tailored treatment of those side effects depending upon their severity.
The researchers also developed a simple, fast method to flag development of neurotoxicity. The 10-point test named CARTOX-10 asks a patient to name the year, month, city, hospital, and president/prime minister of their home country (5 points), to name three nearby objects (3 points), write a standard sentence, and count backward from 100 by tens. A perfect score defines normal cognitive function. A patient has mild to severe impairment depending on the number of questions or activities missed.
For one patient treated for B cell lymphoma cited in the review, deterioration of her handwriting was the first sign of neurological impairment, which led to prompt intervention and reversal of the toxicity within hours.
The authors also tap existing research published or presented about these therapies. For example, CAR T-cell pioneer Carl June, MD, and colleagues at the University of Pennsylvania found abundant expression of interleukin (IL)-6 to be a driver of cytokine release syndrome. They successfully treated the first pediatric patient who suffered from CRS with IL-6 suppressors.
The review provides detailed guidance on how and when to use such drugs and other therapies for CRS and CRES.
Precise causes of these side effects are unknown and remain under investigation. Researchers also are trying to work out what factors allow strong responses in some patients and resistance to treatment or relapse in others.
The algorithms also will be applicable to other types of cell-based immunotherapy, including CAR natural killer cells, T-cell receptor (TCR) engineered T cells, and combination drugs that use an antibody to connect T cells to targets on cancer cells, Shpall said.
Source: MD Anderson; September 19, 2017.