What Is CAR T-Cell Therapy?

New Therapy Produces Remarkable Responses in Early Trials

Cancer research

Formally known as adoptive cell transfer (ACT), this is a new therapy which involves engineering the patients’ own immune cells to recognize and attack their tumor cells. Although this type of therapy is currently experimental and has been restricted to a few small clinical trials so far, it has shown some remarkable responses in patients with advanced cancer.

How It Works

T-cells, a type of immune cell, are present with receptors on their surface, called T-cell receptors, or TCRs. Typically these TCRs bind to antigens to mount an immune response. In an attempt to use T-cells for cancer therapy, T-cells are collected from a patient’s own blood. Then, in the laboratory, the T-cells are modified to produce special receptors on their surface called chimeric antigen receptors, or CARs, which are able to bind to certain surface proteins of particular cancer cells.

The engineered CAR T-cells are harvested in the lab and allowed to increase their numbers until there are billions of them. Subsequent to the modification and harvesting, these T-cells, which present with CARs that can recognize and kill specific cancer cells, are reintroduced into the patient.

These CARs are proteins that let the T-cells recognize a specific protein, or antigen, on tumor cells. So far, how well they work seems to depend at least in part on their ability to grow and remain active in the patient after they get infused back in.

The idea of using live cells to treat cancer is actually not new. Lessons learned from results of similar therapies in the past led to gains in knowledge of how T-cells work, which fueled more discoveries. Investigators working in this field caution that there is still much to learn about CAR T-cell therapy. But the early results from trials like these have generated quite a bit of optimism.

Successes So Far

Some have likened this kind of therapy to the merging of two separate kinds of treatment: targeted antibodies, like rituximab, with their characteristic specificity; and cancer-cell-killing agents with the power of cytotoxicity--all of this with the added long-term presence of living cytotoxic T-cells, to hopefully remain in circulation, monitoring for recurrence.

The research is still very new, so experts urge caution. There are currently two FDA-approved CAR-T cell therapies.

Tisagenlecleucel (Kymriah™) was approved for the treatment of patients up to age 25 with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse. Tisagenlecleucel was the first CAR-T cell approved by the FDA, and the first gene therapy approved in the United States. Acute lymphoblastic leukemia is the most common type of malignancy in children in the United States, and the most common cause of cancer death in children. The B-cell precursor subtype occurs in approximately 82 percent of children with ALL. Tisagenlecleucel was approved based on a single study of 63 patients with relapsed or refractory pediatric precursor B-cell ALL. The remission rate was 83 percent.

Axicabtagene ciloleucel  (Yescarta™) was approved for patients with large-B-cell lymphomas whose cancer has progressed after receiving at least two prior treatment regimens. Large B-cell lymphomas include four different types of lymphomas:

  • diffuse large B-cell lymphoma (DLBCL), the most common lymphoma type
  • primary mediastinal large B-cell lymphoma
  • high-grade B-cell lymphoma
  • and transformed follicular lymphoma

More than 100 patients with large B-cell lymphomas were enrolled in the trial that led to the approval, called ZUMA-1. Approximately half of the patients had a complete response to the treatment—that is, their cancer disappeared completely. And nearly 30 percent of patients had a partial response, some reduction in the extent of their disease.

Investigators hope CAR T-cell therapy will one day become a standard therapy for certain B-cell malignancies such as ALL and chronic lymphocytic leukemia. Researchers working with CAR-T-cells have also identified this kind of therapy as a “bridge” to bone marrow transplant for ALL patients who stop responding to ch.emotherapy.

 CAR T-cell therapy it is currently being tested in relapsed and refractory non-Hodgkin lymphoma, myeloma, and chronic lymphocytic leukemia (CLL), other types besides large B-cell lymphoma of relapsed and refractory non-Hodgkin lymphoma and in solid tumors (for example, melanoma).

There is also the hope that CAR T-cell therapy might be used to prevent relapses. Other findings that serve to fuel optimism include expansion of the treatment cells after infusion, as much as 1,000-fold in some individuals; and the presence of CAR T-cells in the central nervous system, a “sanctuary site” where lone cancer cells that have escaped chemotherapy or radiation may hide. In two patients in an NCI-led pediatric trial, for instance, the CAR T-cell treatment eradicated cancer that had spread to the central nervous system.

Side Effects

When a large number of engineered T-cells are reintroduced in a patient, these T-cells release cytokines in large amounts. This may cause the cytokine-release syndrome, which is characterized by dangerously high fevers and drop in the blood pressure. Cytokines are chemical signals, and cytokine-release syndrome is a common problem in patients treated with CAR T-cells.

Patients with the most extensive involvement of cancer prior to receiving the CAR T-cells appear more likely to have the severe cases of cytokine-release syndrome. Researchers caution that despite successes, more research is needed before CAR T-cell therapy can becomes a routine option, for patients with ALL for instance. Studies with more patients and longer follow up periods have been called for and pursued.

On the Horizon

Based on the success thus far, several research groups across the country are turning their attention to developing engineered T-cells for other cancers, including solid tumors like pancreatic and brain cancers.

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