CAR T-Cells in Leukemia: Expert Commentary

Zosia Chustecka

October 16, 2014

This week has seen the publication of dramatic results from two studies with chimeric antigen receptor (CAR)-modified T-cells in the treatment of refractory and/or relapse acute lymphoblastic   leukemia (r/rALL), as reported by Medscape Medical News in "CARs Motor Through Leukemia, Can 'Eradicate' Disease," Part 1 and Part 2.

                                                               

Dr Catherine Bollard

                       

Now we catch up with Catherine Bollard, MD, from the Children's National Medical Center in Washington, DC, who will be presenting an educational session about CAR T-cell therapy at the American   Society of Hematology (ASH) annual meeting in December 2014. She has not been involved in these two studies, and was approached for comments about the new results.

Medscape Medical News: How do these results in r/rALL compare with what is seen typically now?

Dr Bollard: T-cell therapies utilizing the CD19 chimeric antigen receptor (CAR) technology are an exciting strategy for the treatment of children and adults with relapsed acute lymphoblastic   leukemia, as was spotlighted effectively at last year's ASH meeting [and was reported by Medscape Medical News at the time].   Furthermore, to emphasize the importance of the field, T-cell therapies are a highlight of the Education Program at ASH's 2014 annual meeting.

For the first time, this novel therapy offers a chance for patients with acute lymphoblastic leukemia to have a significant clinical benefit even in a patient population who have failed all   other proven as well as experimental therapies and were previously thought to have no treatment options left.

In particular, if a patient relapses after allogeneic bone marrow transplant, this is often considered a death sentence.

Therefore, the clinical responses seen using CD19-CAR-modified T-cells has been a dramatic turnaround in the prospects for these unfortunate patients. Furthermore, it can give patients the   chance to achieve a remission and to go on and receive a potentially curative bone marrow transplant.

Medscape Medical News: Are you excited about this investigational approach?

Dr Bollard: This is an exciting investigational approach. But we still need to be cautious, because these therapeutic responses are associated with potentially life-threatening toxicities.   Therefore, while we as treating clinicians are highly excited when we see dramatic clinical responses in our individual patients, as physician scientists, we have to temper our enthusiasm for a   novel technology and the reality of where we are at the present time.

Like all new trials, the phase 1 studies are absolutely critical. And these early results from the groups at Children's Hospital of Philadelphia and University of Pennsylvania (as highlighted   by the recent article in the New England Journal of Medicine [2014;371:1507-1517], which is an extension of their patient report   previously published in the same journal) and the National Cancer Institute/National Institutes of Health group (published online in the Lancet October 10 as the first intention-to-treat CD19-CAR T-cell study) further strengthens our perceptions   that these are highly potent cancer-killing cells.

Furthermore, these data build on previously published work utilizing CAR–T-cells for the treatment of pediatric and adult cancers, as has also been demonstrated by many other groups, such as   Memorial Sloan Kettering Cancer Center, Baylor College of Medicine, Fred Hutchinson Cancer Center/Seattle Children's,  City of Hope, and other branches within the NIH.

Medscape Medical News : Do you think it has potential to be a treatment?

Dr Bollard: While this has the potential to be a treatment, it has not yet proven to stand on its own as a single-agent curative approach, and like most therapies for cancer, it should best be   considered as part of a multimodality treatment approach. The ultimate strategy would be to combine CAR T-cells with other targeted cancer treatments, such as small molecule inhibitors,   antibodies, checkpoint inhibitors, etc.

Medscape Medical News: Do you see a future for this in mainstream medicine? Or will it be a therapy that will be offered only to a few very lucky patients who can access top-  rate cancer clinics?

Dr Bollard: Until advances are made in the engineering of the CAR T-cells to render the technology safer, then it may be difficult for this treatment to become a mainstream therapy. Since this   treatment is currently limited by its toxicity profile, numerous investigators nationally and internationally are exploring different modifications to increase the safety of the CAR T-cells.   Furthermore, industry is now becoming interested in these technologies, and multicenter studies are planned. The involvement of industry is essential before these technologies will   become so-called "mainstream medicine."

In addition, it is important to note that other T-cell-mediated therapies are being developed, such as the BITE antibodies and multiantigen-specific T-cells. And some of these therapies have   also shown significant promise clinically for some of our patients with the poorest prognosis. Therefore, we should be open to all these developments. Breakthroughs in other lines of therapeutic   development might again change the direction in which we alter our approaches for the treatment of cancer. Or add an even stronger armamentarium. Therefore, it is critical we keep an open   mind.

Medscape Medical News: What about the adverse events and cytokine release syndrome, etc. Is this a big problem?

Dr Bollard: A treatment that has less immediate toxicity would definitely be desirable, especially considering the concern that very sick patients are being treated with this therapy and   developing life-threatening toxicities that would be considered far more severe than is typically seen with chemotherapy or even with bone marrow transplantation. Therefore, while the results from the   CD19-CAR T-cell studies are indeed promising, we have to carefully watch for these extreme toxicities. Furthermore, we are still waiting for the long-term efficacy data, and it is still too early   to say whether or not CD19-CAR T-cells offer a potentially curative treatment.

In addition, one potential problem with CD19-CAR T-cell therapy is the limitation of targeting a single-surface antigen, especially as highlighted by the proportion of patients (10%) who   relapsed with CD19-negative acute lymphoblastic leukemia. This emphasizes  that, for those patients, you only get one chance with this therapy, and explains why the Leukemia Lymphoma Society has funded   groups at Children's National and Baylor College of Medicine to focus on a multiantigen T-cell therapy for patients with ALL  to avoid this immune escape mechanism.

Dr Bollard reports no relevant financial relationships.

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