What is CAR T-Cell Therapy?
Formally known as adoptive cell transfer (ACT), this is a fresh therapy which involves engineering the patients’ own immune cells to recognize and attack their tumor cells. Albeit this type of therapy is presently experimental and has been restricted to a few puny clinical trials so far, it has shown some remarkable responses in patients with advanced cancer.
T cells, a type of immune cell, are present with receptors on their surface, called T-cell receptors, or TCRs.
Typically these TCRs truss to antigens to climb on 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 truss to certain surface proteins of particular cancer cells. The engineered CAR T cells are harvested in the lab and permitted 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. The engineered CAR T cells are grown up in the lab and permitted to increase their numbers until there are billions of them.
So far, how well they work seems to depend at least in part on their capability 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 fresh. Lessons learned from results of similar therapies in the past led to gains in skill 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 fairly 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 fresh, so experts urge caution, but clinical trials have already begun using CAR T-cell therapies in the following cancers:
- Advanced melanoma
- Advanced acute lymphoblastic leukemia (ALL)
- Diffuse large B-cell lymphoma
The FDA has designated CAR T-cell therapy a breakthrough therapy for ALL. It’s also being tested in relapsed and refractory non-Hodgkin lymphoma, myeloma, and chronic lymphocytic leukemia (CLL), as well as for patients with non-Hodgkin lymphoma and myeloma.
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 chemotherapy.
One trial examined the use of CAR T cells in fifteen adult patients, and most of them had advanced diffuse large B-cell lymphoma. However it was undoubtedly a petite trial, optimism comes from the fact that most of these patients treated with CAR T-cells had either finish or partial responses.
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 jumpy 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 example, the CAR T-cell treatment eradicated cancer that had spread to the central jumpy 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 unsafely 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 emerge 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 example. Studies with more patients and longer go after 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.
Barrett DM, Singh N, Porter DL, Grupp SA, June CH. Chimeric Antigen Receptor Therapy for Cancer. Annu Rev Med. 2014;65:333-347.