Chimeric Antigen Receptors in CLL
By now many of you have seen the news articles regarding the University of Pennsylvania CLL study. The results, recently published in the New England Journal of Medicine and Science Translational Medicine describes dramatic responses in three patients with chronic lymphocytic leukemia (CLL) who had very advanced and treatment-resistant CLL. Dr. Carl June and his collaborators, along with other investigators around the country, have pioneered the expansion of T-cells . By inserting genetic material into T-cells, the T-cells express a chimeric antigen receptor (CAR) on their surface, which can then specifically target the T-cells to kill CLL cells.
These CARs specifically recognize proteins on the surface of CLL cells. After the CAR positive T-cells (CAR+ T-cells) bind to their specific target, the T-cells are triggered to attack and kill the CLL cells. As such, they have become highly specific and efficient killers of CLL cells. These CAR+ T-cells are also capable of multiplying in the body. The CAR tested in the UPenn study targets the CD19 antigen, which is a protein on the surface of the majority of B-cells, including CLL cells.
The process of developing these CAR+ T-cells is cumbersome, expensive and tightly regulated. However, it is a great opportunity to use the patient's own immune cells to eradicate reigning leukemic cells. At the time the journal article was written, the response or remissions were at 10 months long. The eventual duration of the response is unknown at the present time. There is optimism that by using the patient's own immune system to create resistance against the CLL cells, patients may have either long remissions or possibly long term control of their disease.
The investigators at UPenn are to be complimented on their commitment to and continued development of cellular immunotherapy over many years. They have pioneered several promising approaches. Other investigators have developed similar approaches to educate the immune system.
A number of investigators in the U.S./European Alliance have also been developing the CAR concept, including collaborators at Baylor College of Medicine in Houston, TX with Gianpietro Dotti being the principal investigator; Laurence Cooper at MD Anderson Cancer Center (MDACC), in collaboration with William Wierda, EJ Shpall, Chitra Hosing and Tom Kipps at University of California, San Diego (UCSD). There are also several other medical research centers around the country exploring CARs. CLL Global grant recipient Renier Brentjens at Memorial Sloan-Kettering is currently evaluating a CAR against CD19. In addition to CD19 as a target, there are CARs being developed to recognize and respond to the ROR1 protein, which is relatively unique to CLL.
There is a rapidly developing national and international interest in the use of T-cells and CARs and many of the investigators looking at immune reconstitution, including Drs. June and Levine, have had their research supported by the CLL Global Research Foundation. CLL Global did not fund the recently publicized research but rather a separate project with Drs. June and Levine using CD3/CD28 beads to make T-cells more effective.
Studies will soon open at MDACC using the CD19 CARs, and future studies targeting ROR1 will be conducted at MDACC and with collaborator Dr. Kipps at UCSD. Patients interested in this concept can continue to note progress with the research on the CLL Global website. They should also feel free to visit the clinicaltrials.gov site for a listing of studies using CARs.
This is a major conceptual advance. Further research and experience is necessary to ascertain the consistency of the CAR+ T-cells clearing the CLL cells, the long term side effects and applicability to a wide range of patients. There are various versions of the CD19 CAR, and multiple versions of the ROR1 CAR will likely be developed. It is uncertain which one will be the most effective. In addition to the UPenn data, other studies testing CARs have been done in lymphomas. Further investigations will need to be conducted in CLL patients.
CARs offer a great advantage over stem cell transplantations from siblings or unrelated donors as there is no graft-versus-host-disease. However, translating this small study with short follow-up into statements of "cure" are certainly premature. This is truly an exciting concept to be blended in with a number of the other rapidly advancing areas in CLL clinical research.