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  • Posted: 12/06/2013

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CAR T-Cell Therapy: Engineering Patients’ Immune Cells to Treat Their Cancers


Illustration of the components of second- and third-generation chimeric antigen receptor T cells. (Adapted by permission from the American Association for Cancer Research:  Lee, DW et al. The Future Is Now: Chimeric Antigen Receptors as New Targeted Therapies for Childhood Cancer. Clin Cancer Res; 2012;18(10); 2780–90. doi:10.1158/1078-0432.CCR-11-1920)
Illustration of the components of second- and third-generation chimeric antigen receptor T cells. (Adapted by permission from the American Association for Cancer Research: Lee, DW et al. The Future Is Now: Chimeric Antigen Receptors as New Targeted Therapies for Childhood Cancer. Clin Cancer Res; 2012;18(10); 2780–90. doi:10.1158/1078-0432.CCR-11-1920)

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For years, the cornerstones of cancer treatment have been surgery, chemotherapy, and radiation therapy. Over the last decade, targeted therapies like imatinib (Gleevec®) and trastuzumab (Herceptin®)—drugs that target cancer cells by homing in on specific molecular changes seen primarily in those cells—have also emerged as standard treatments for a number of cancers.

And now, despite years of starts and stutter steps, excitement is growing for immunotherapy—therapies that harness the power of a patient’s immune system to combat their disease, or what some in the research community are calling the “fifth pillar” of cancer treatment.

One approach to immunotherapy involves engineering patients’ own immune cells to recognize and attack their tumors. And although this approach, called adoptive cell transfer (ACT), has been restricted to small clinical trials so far, treatments using these engineered immune cells have generated some remarkable responses in patients with advanced cancer.

Although adoptive cell transfer has been restricted to small clinical trials so far, treatments using these engineered immune cells have generated some remarkable responses in patients with advanced cancer.

In several small ongoing phase I trials testing ACT in patients with advanced acute lymphoblastic leukemia (ALL), for example, most patients’ cancers disappeared entirely. Several of these patients have remained cancer free for extended periods. Two of the trials primarily included children with ALL, and patients in all three trials had few if any remaining treatment options.

Equally promising results have been reported in trials involving patients with lymphoma.

These are small clinical trials, their lead investigators cautioned, and much more research is needed.

But the results from the trials performed thus far “are proof of principle that we can successfully alter patients’ T cells so that they attack their cancer cells,” said one of the trial’s leaders, Renier J. Brentjens, MD, PhD, of Memorial Sloan-Kettering Cancer Center (MSKCC) in New York.

“A Living Drug

Adoptive cell transfer is like “giving patients a living drug,” continued Dr. Brentjens, who led the adult ALL trial.

That’s because ACT’s building blocks are T cells, a type of immune cell collected from the patient’s own blood. After collection, the T cells are genetically engineered to produce special receptors on their surface called chimeric antigen receptors (CARs). CARs are proteins that allow the T cells to recognize a specific protein (antigen) on tumor cells. These engineered CAR T cells are then grown in the laboratory until they number in the billions. (See the box below.)

The expanded population of CAR T cells are then infused into the patient. After the infusion, if all goes as planned, the T cells multiply in the patient’s body and, with guidance from their engineered receptor, recognize and kill cancer cells that harbor the antigen on their surfaces.

Constructing a CAR T Cell 

The first efforts to engineer T cells to be used as a cancer treatment began in the early 1990s. Since then, researchers have learned how to produce T cells that express chimeric antigen receptors (CARs) that recognize specific targets on cancer cells. 

The T cells are genetically modified to produce these receptors. To do this, researchers use viral vectors that are stripped of their ability to cause illness but that retain the capacity to integrate into cells’ DNA to deliver the genetic material needed to produce the T-cell receptors. 

The second- and third-generation CARs typically consist of a piece of monoclonal antibody, called a single-chain variable fragment (scFv), that resides on the outside of the T-cell membrane and is linked to stimulatory molecules (Co-stim 1 and Co-stim 2) inside the T cell. (See the image at the top of the page.) The scFv portion guides the cell to its target antigen. Once the T cell binds to its target antigen, the stimulatory molecules provide the necessary signals for the T cell to become fully active. In this fully active state, the T cells can more effectively proliferate and attack cancer cells. 

Researchers are still improving how CAR T cells are produced, including testing various delivery vectors and different stimulatory molecules to see which can help produce the most potent T cells. 

Production used to take as long as a month, but now researchers at NCI and the other centers involved in this work can produce an infusion-ready product in 9 to 13 days.

Steven Rosenberg, MD, PhD, and his colleagues from NCI’s Surgery Branch pioneered a slightly different form of ACT in patients with advanced melanoma. And the researchers have reported success with CAR T cells in small clinical trials of patients with leukemia and lymphoma. At the American Society of Hematology (ASH) annual meeting in December 2013, James Kochenderfer, MD, of NCI’s Experimental Transplantation and Immunology Branch presented updated results from a trial using  T cells taken from patients, as well as results from one of the first trials testing CAR T cells derived from donors rather than the patients themselves.

The CAR T cells are “much more potent than anything we can achieve” with other immune-based treatments being studied, said Crystal Mackall, MD, of NCI’s Pediatric Oncology Branch.

Even so, 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 considerable optimism.

CAR T-cell therapy eventually may “become a standard therapy for some B-cell malignancies” like ALL and chronic lymphocytic leukemia, Dr. Rosenberg recently wrote in a Nature Reviews Clinical Oncology article.

A Possible Option Where None Had Existed

More than 80 percent of children who are diagnosed with ALL that arises in B cells—the predominant type of pediatric ALL—will be cured by intensive chemotherapy.

For patients whose cancers return after intensive chemotherapy or a stem cell transplant, the remaining treatment options are “close to none,” said Stephan Grupp, MD, PhD, of the Children’s Hospital of Philadelphia (CHOP), who leads one of the pediatric trials testing CAR T cells. This treatment may represent a much-needed new option for such patients, he said.

In the two pediatric trials of CAR T cells, the patients were treated with T cells engineered to target the CD19 antigen, which is present on the surface of nearly all B cells, both normal and cancerous.

Updated results from the trials were also presented at the 2013 ASH annual meeting.  

In the CHOP trial, which is being conducted in collaboration with researchers from the University of Pennsylvania, all signs of cancer disappeared (a complete response) in most of the patients treated thus far (16 children and 4 adults to date), according to the most recent data. Cancer has returned in 3 of these patients, but overall 11 of the 17 evaluable patients who had complete responses have remained cancer free.

[The CAR T cells are] much more potent than anything we can achieve [with other immune-based treatments being studied].

—Dr. Crystal Mackall

In the pediatric trial conducted at NCI by Daniel W. Lee, MD, 9 of the 15 patients reported thus far (14 with ALL and 1 with non-Hodgkin lymphoma) have had complete responses, according to the updated results. Due to poor expansion of the T cells during the production process, two patients have received a far smaller dose of the engineered cells than the other patients; in both cases, however, those patients responded to the treatment.

Similar results were seen in the trial of adult patients led by Dr. Brentjens. In the findings presented the at the ASH meeting, 10 of the 13 patients treated thus far have had complete responses, which in some cases occurred 2 weeks or sooner after treatment began.

The NCI trial of CAR T cells presented by Dr. Kochenderfer at the ASH annual meeting included 15 patients with leukemia or lymphoma. Most of the patients in the trial had either complete or partial responses, he reported.

“Our data provide the first true glimpse of the potential of this approach in patients with aggressive lymphomas that, until this point, were virtually untreatable,” Dr. Kochenderfer said in a news release.

Other findings from the trials have been encouraging, as well. For example, the number of CAR T cells increased dramatically after infusion into patients, as much as 1,000-fold in some individuals. In addition, after infusion, CAR T cells were detected in the central nervous system, a so-called sanctuary site where solitary cancer cells that have evaded chemotherapy or radiation may hide. In the NCI trial, the CAR T cell treatment cleared disease that had spread to the central nervous system, Dr. Lee said.

Persistence of CAR T cells at these sites could help fend off relapses, Dr. Mackall stressed.

Managing Unique Side Effects

CAR T-cell therapy can cause several worrisome side effects, perhaps the most troublesome being cytokine-release syndrome.

The infused T cells release cytokines, which are chemical messengers that help the T cells carry out their duties. With cytokine-release syndrome, there is a rapid and massive release of cytokines into the bloodstream, which can lead to dangerously high fevers and precipitous drops in blood pressure.

Several patients in the three trials experienced a cytokine-release syndrome. In most patients the problems were mild enough that they could be managed with standard supportive therapies, including steroids.

In some other patients, however, the debilitating fevers and drops in blood pressure required additional measures. The research team at CHOP noticed that these patients all had particularly high levels of IL-6, a cytokine that is secreted by T cells and macrophages in response to inflammation. So they turned to two drugs that are approved to treat inflammatory conditions like juvenile arthritis: etanercept (Enbrel®) and tocilizumab (Actemra®), the latter of which blocks IL-6 activity.

The patients had “excellent responses” to the treatment, Dr. Grupp said. “We believe that [these drugs] will be a major part of toxicity management for these patients.”

The other two teams have subsequently used tocilizumab in several patients. Dr. Brentjens agreed that both drugs could become a useful way to help manage cytokine-release syndrome because, unlike steroids, they don’t appear to affect the infused CAR T cells’ activity or proliferation.

Improving the Process

Even with these encouraging preliminary findings, more research is needed before CAR T-cell therapy becomes a routine option for patients with ALL.

“We need to treat more patients and have longer follow-up to really say what the impact of this therapy is [and] to understand its true performance characteristics,” Dr. Grupp said.

All three research groups continue to enroll patients in their respective trials, even as they plan future trials and new efforts to improve on the positive results obtained to date, including improving the process by which the CAR T cells are produced.

We need to treat more patients and have longer follow-up to really say what the impact of this therapy is [and] to understand its true performance characteristics.

—Dr. Stephan Grupp

Research groups like Dr. Brentjens’ are also working to make a superior CAR T cell, including developing a better receptor and identifying better targets.

For example, Dr. Lee and his colleagues at NCI have developed CAR T cells that target the CD22 antigen, which is also present on most B cells, although in smaller quantities than CD19. The CD22-targeted T cells, he believes, could be used in concert with CD19-targeted T cells as a one-two punch in ALL and other B-cell cancers. NCI researchers hope to begin the first clinical trial testing the CD22-targeted CAR T cells in early 2014.

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.

The stage has now been set for greater progress, Dr. Lee believes.

NCI investigators, for example, “now have a platform to plug and play better CARs into that system, without a lot of additional R&D time,” he continued. “Everything else should now come more rapidly.”

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