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SPECIAL EDITION: CHIMERIC ANTIGEN RECEPTORS (CARs)

 

August 2011 

Greetings!

 

Recent media coverage on chimeric antigen receptors (CARs) has caused quite a stir in the CLL community, and with good reason. CLL physicians' phones have been ringing off the hook and email inboxes have been filling up with questions from patients. You want to know what these CARs are, if they are really the smoking gun and when they will be available to you for treatment. We are addressing your questions with a special issue of Tidbits about CARs. 

KEATING'S INSIGHTS ON THE BREAKTHROUGH RESEARCH

  

Chimeric Antigen Receptors in CLL

 

Dr. Michael Keating 

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.

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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. 

ANSWERING YOUR QUESTIONS

  

Dr. William Wierda

 

Dr. William Wierda, Associate Professor in the Department of Leukemia at Medicine at MD Anderson Cancer Center, is actively exploring immune therapy approaches for CLL. Below he provides answers to some of your common questions about CARs.

 

When will CARs be available to all patients?

There is still significant work needed in clinical trials and research in the CAR technology and clinical application before this becomes a treatment that can be generally applied to patients with CLL in the community. This is all necessary to assure that it is a safe and effective treatment. When we know it is safe and know how best to give it to patients, it will become generally available. Because it involves taking the patients' own T-cells and modifying them to express the CAR gene, it requires patients' cells to be manipulated in highly specialized laboratory facilities. This is very different than providing a pill or IV medication that can be dispensed by a pharmacy or from a clinic or hospital. So, there are many logistic hurdles to making this available to all patients in the community.

 

Because of the recent publicity, will the FDA fast track CARs for therapy?

I don't expect that there will be special treatment or consideration for CAR development by the Food and Drug Administration (FDA). The FDA has a specific process for developing drugs to assure safety and to demonstrate that treatments are effective. Experimental therapies, and this is a very experimental therapy, do not get special treatment just because they look promising or make big headlines. The FDA typically requires researchers to follow guidelines and take necessary precautions for the safety of patients.

 

When will this pass FDA approval?

It will probably take several years for this to happen, but we cannot provide an exact answer at this time. There are many variables that go into FDA approval: pharmaceutical companies get involved with their objectives and agenda, the feasibility is an issue, the short and longer term safety, and many other issues. CARs are a specialized treatment. This type of treatment has to be done at a specialized center with the technology to genetically engineer the T-cells.

 

Are there any studies patients can have access to now?

There are several groups around the country studying CD19 CARs including the investigators at UPenn, MD Anderson Cancer Center, National Cancer Institute, Memorial Sloan-Kettering, and Baylor University. There is limited published information thus far, indicating that this is early in clinical development. Currently, the best way to determine if there are clinical trials with CARs is to go to www.clinicaltrials.gov and search for such trials. According to UPenn, their trial is currently on hold and not immediately enrolling additional patients. As it reopens in the next few months, only a very few patients will be able to be treated. Patients can continue to check with UPenn on the accrual status or call one of the other centers mentioned above who are working on this treatment. We are working on opening trials at MDACC soon but none are open at the moment.

 

If a patient has already had treatment, is CAR therapy still an option?

Yes. For the clinical trials, most patients will probably have to be previously treated with standard treatments before they are eligible for clinical trials. The three patients already tested at Upenn were refractory to standard treatments, and appear to have responded well to the therapy.

 

FOR MORE INFO

  

Articles from UPenn Study: 

 

Recent Media Coverage: 

 Clinical Trials: 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
THANK YOU FOR SUPPORTING US!

We hope this special issue has answered some of your questions. The next issue of the CLL Research Momentum will contain more information on CARs, inlcuding an interview with Dr. Cooper regarding his reasearch with CARs.    

           

Sincerely,


CLL Global Research Foundation