Success of T-cell therapy in hematologic malignancies cause for optimism, concern

When researchers announced that multiple patients with leukemia who had been treated with genetically engineered T cells experienced fast and durable remission, the findings sent shockwaves through the scientific community.

All patients received a lentiviral vector that expressed a chimeric antigen receptor with specificity for the B-cell antigen CD19, paired with CD137 and CD3-zeta signaling domains.

The therapy induced response in nine of the 12 patients, including four who achieved complete response and remained in remission 2 years after treatment.

“The findings were so dramatic,” Kanti R. Rai, MD, chief of the CLL research and treatment program at North Shore — Long Island Jewish Medical Center, professor of medicine at Hofstra North Shore–LIJ College of Medicine and a 
HemOnc Today Editorial Board member, said in an interview with HemOnc Today. “In the first paper in 2011, we learned about a man with virtually one-and-a-half feet in the grave. Within a matter of 3 months, he was in complete remission. A similar phenomenon was presented during this group’s report at the recent ASH Annual Meeting. Suddenly everyone took notice in B-cell malignancies.”

The use of chimeric antigen receptor–modified T cells is not a new approach in cancer research. The concept has been explored in medical literature for nearly 2 decades, and it has been the subject of trials at NCI, Baylor University, City of Hope and several other sites.

“We have been doing research in this area for more than 10 years,” Michel Sadelain, MD, PhD, of the molecular pharmacology and chemistry program, the Center for Cell Engineering, the Experimental Therapeutics Center and the Center for Stem Cell Biology at Memorial Sloan-Kettering Cancer Center, told HemOnc Today. “But it was the results from Drs. Porter and June that captured the imagination of people who had not heard about this approach before.”

Still, questions remain. It is unclear why the approach used by Porter and colleagues was more successful than others, if the technique can be replicated on a larger scale and whether it holds potential for other malignancies, including solid tumors. There also are concerns about the cost, transportability and adverse events associated with autologous T-cell therapy.

HemOnc Today spoke with several clinicians and researchers who agreed that, although they are encouraged by recent progress, there still is much work to be done.

The numbers game

In the study by Porter and colleagues, patients with refractory CLL received a 1.5 x 10⁵ cells per kg of body weight dose of modified T cells. The dose was expanded to more than 1,000 times as high as the initial engraftment in vivo, according to the researchers.

The infusion on day 0 involved an infusion of a median of 7.5 x 10⁸ total cells (range, 1.7-50) corresponding to 1.45 x 10⁸ (range, 0.14-5.9) genetically modified cells.

“They identified an effective number of T cells to administer,” Michael Grever, MD, program leader for experimental therapeutics at the Ohio State University Comprehensive Cancer Center — Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and chair of the department of internal medicine at Ohio State University Wexner Medical Center, told HemOnc Today. “This is not to be underestimated because, if you have a fight going on and the enemy outnumbers you, it’s hard to win the war. If you have sufficient T cells to fight the battle, you can win.”

Eligible participants had persistent disease after undergoing at least two treatment regimens.

The autologous T cells used in the analysis had been collected by leukapheresis. The cells were transduced with a lentivirus encoding anti-CD19 scFv linked to 4-1BB and CD3-z signaling domains, according to the researchers.  The modified cells were expanded and activated ex vivo by exposure to anti-CD3/CD28 beads.

“Perhaps the 4-1BB signal is durable enough to enable a sustained attack against a large tumor burden, which we see in CLL,” Sadelain said.

The median number of previous treatments administered to patients in the CLL group was five (range, 2-10). All patients had active disease when clinicians administered the infusion and had received lymphodepleting chemotherapy 4 to 6 days before infusions. One-third of the CLL cohort had disease with a p53 deletion.

One of the children with ALL had chemorefractory relapsed disease and was treated with chemotherapy 6 weeks before the infusion.

“Patients were conditioned with bendamustine, to which the patients were sensitive,” Sadelain said. “This teaches us that using an agent to which the tumor is sensitive may be very important, and that chemotherapy conditioning is likely integral to outcomes.”

Durable remission

By day 23 of the study by Porter, June and colleagues, five patients — three adults in the CLL group and the two children with ALL — demonstrated a complete response. Four patients in the CLL group demonstrated partial response.

The findings signify the first sustained demonstration that gene therapy can turn the body’s immune cells can be converted into a weapon against cancerous tumors, the researchers said.

“Our results show that chimeric antigen receptor modified T cells have great promise to improve the treatment of leukemia and lymphoma,” June, the Richard W. Vague professor in immunotherapy in the department of pathology and laboratory medicine and director of translational research at Penn’s Abramson Cancer Center, said in a press release. “It is possible that in the future, this approach may reduce or replace the need for bone marrow transplantation.”

The patients who demonstrated complete response showed maximal expanded cells in the blood. The researchers detected these at an average of 27-fold (range, 21-fold to 40-fold) higher than the infused dose. These patients also demonstrated elevations from baseline in interferon-gamma, interleukin-6 and IL-2R, but no significant elevation in tumor necrosis factor-alpha or IL-2.

No relapses have been reported among the patients who demonstrated complete response.

“There appear to be two keys to this result. One is that cytokines are made, and the other is that the T cells proliferate,” said Laurence J.N. Cooper, MD, PhD, who was involved with the study by Porter and colleagues.

“The proliferation is the finding that we feel is most significant. When their T cells were administered to the recipient, they synchronously activate and numerically expand,” Cooper, professor in pediatrics at The University of Texas MD Anderson Cancer Center and section chief of cell therapy at Children’s Cancer Hospital, said in an interview.

That expansion is responsible for the durability of the remission, according to Mitchell Smith, MD, PhD, director of lymphoid malignancies at Cleveland Clinic Taussig Cancer Institute.

“What is impressive is that these cells have persisted, expanded and grown for a long time,” Smith said. “These cells continue to kill off cells that express CD19.”

Most clinicians, including Smith, agree that such results will not occur in all 
patients.

“But it certainly is exciting if you are a responder,” he said.

The clinical challenge is to identify why certain patients in the Porter study and other investigations responded to this therapy and others did not.

“We are all analyzing those data, trying to figure out what the differences were between the responders and the nonresponders, and why — after years of attempting this strategy — this result was achieved in this particular subset of patients,” Sadelain said. “There have not been enough patients treated yet to obtain statistically robust biological and clinical correlative data.”

Data comparisons

A review article by Davila and colleagues published last year in Oncoimmunology summarized data from six clinical trials that investigated the use of T cells to target CD19+ malignancies. They reported data for 28 patients, including 22 with CLL.

A study by Jensen and colleagues published in 2010 in Biology of Blood and Bone Marrow Transplantation described two patients with relapsed follicular lymphoma who developed progressive disease within 6 months of the last T-cell infusion.

A study by Salvodo and colleagues published in the Journal of Clinical Investigation evaluated 20 patients with indolent or aggressive lymphoma. The longest duration of response among those patients was 10 months.

A group at NCI reported on four patients with CLL, three with follicular lymphoma and one with marginal zone lymphoma. One patient achieved complete response, and the others demonstrated partial responses.

Members of the research community must investigate several factors to determine why the responses in Porter’s group were so much more significant.

“We are looking at differences in the chimeric antigen receptors, the molecular makeup of the receptor in the T cells, differences in the manufacturing process, differences in the way the cells are delivered to the patients and differences in chemosensitivity,” Sadelain said. “We are all trying to read into the tea leaves.”

Most experts agree that the advent of second-generation chimeric antigen receptors was a turning point, but questions remain about how to use them to optimal capacity.

“At Sloan-Kettering, we have used CD28-based CARs [chimeric antigen receptors] with success in adults with ALL,” Sadelain said. “4-1BB–engineered T cells appear to be slower to start and more durable, while CD28 is rapid but less durable, thus increasing T-cell effectiveness against larger tumor burdens. At NCI, however, a CD28 chimeric antigen receptor was used in conjunction with more robust conditioning and achieved a complete remission in a patient with CLL.”

Adverse events

Patients who have responded to T-cell therapy have experienced some equally dramatic adverse events. Porter and colleagues reported no deaths or ≥grade 3 toxicities among patients in their group, but they did report a flu-like cytokine release syndrome in all responders.

This syndrome was successfully treated with anti-cytokine therapy.

“We saw a second level of toxicity in the infusion of T cells,” Cooper said. “This cytokine storm caused patients to get sick.”

Tumor lysis syndrome and associated transient kidney injury have been reported along with the cytokine release syndrome, Grever said.

“Current studies are investigating ways to combat these events,” he said. “We are working with a drug that may combat the tumor lysis syndrome and the kidney injury. The good news is that these clinical consequences are challenging but not necessarily insurmountable. Also, the tumors are going away, which is most important.”

T cells also can be too successful killing B cells, Rai said.

“If they are unable to recognize the difference between malignant and nonmalignant cells, patients can lose all of their B cells,” he said. “These patients may be susceptible to pneumonia and other diseases.”

Immunoglobulin injections have been successful in providing some protection, but clinicians should be aware of the possibility, Rai said.

“This shoe is likely to drop,” he said. “The more patients we see who lose all their B cells, the more likely it will be that we will have to deal with the consequences of severely immunosuppressed state.”

Meir Wetzler, MD, FACP, chief of the leukemia section in the department of medicine and professor of medicine at Roswell Park Cancer Institute, offered a potential solution.

“If these cells stay there forever, it certainly could become a problem,” he said. “The cells should have a suicide gene. When the patient reaches a durable remission, a course of therapy with something like tetracycline could trigger a suicide gene in the T cells. This is something we are working on.”

Operational challenges

There also are logistical concerns that extend beyond the clinic.

“It’s easy to pack a pill or an IV drug,” Grever said. “This is a much more complex technology. We are still waiting to see whether these operational challenges can be easily or readily fixed, and how transportable this process is.”

It is imperative that all potential risks associated with the procedure be resolved before attempting to take it from one institution to another, according to Grever.

“If you export things before they are ready, before measures have been taken to make it safe, you can kill it,” he said. “It will need to be perfected in one institution first, and then we can work on transporting it.”

Wetzler expanded on that point.

“Perfection should always be our goal, but sometimes we should also consider areas of great need,” he said. “If we continue to see success with T-cell therapy, we should begin working on developing cells that go after other malignancies. There may be opportunities to treat AML and other lymphomas this way.”

Researchers also said this approach may hold promise for treatment of some solid tumors.

Protocols have been designed to evaluate how well this approach targets the protein mesothelin in patients with mesothelioma, pancreatic cancer and ovarian cancer. Protocols also are in development for patients with prostate cancer and breast cancer.

At the moment, only the most sophisticated laboratories have the capability to engineer T cells for this purpose.

Most academic institutions have the capability to collect T cells. However, engineering T cells to express the genes that will make them effective is a different story, Grever said.

Also, different laboratories engineer cells in different ways, which makes standardizing regimens and predicting outcomes extremely difficult.

“Each center has their manufacturing process, and that complicates comparisons,” Sadelain said. “We will need to see a collaborative study to learn why some processes are better than others.”

Lack of resources

Despite these obstacles, a collaborative study — supported by the NCI — is under way involving researchers at Penn and Memorial Sloan-Kettering Cancer Center, Sadelain said.

Researchers are infusing patients with a 50/50 combination of cells made at the two centers.

Sadelain said he is optimistic about the study but noted there have been difficulties in finding funding for such collaborative projects.

Academic and industry partnerships must be developed around this approach, Cooper said.

“Industry is taking notice but, at the moment, it is still a boutique therapy, meaning that we can only treat handfuls of people this way,” he said. “We will need more backing if it is going to be used more broadly.”

The paucity of resources is a concern faced by the entire medical community, Wetzler said.

“A byproduct of a poor US economy is that support for health care is decreasing across the board, particularly for risky and expensive initiatives such as this,” he said. “Without support, we will never get the answers we need. Congress should be aware of where things are with this therapy.”

There also are issues associated with administering an autologous product that tie into the resource problem, Cooper said.

“T cells have been given as an off-the-shelf therapy,” he said. “This may help stretch scarce resources but will need to be regulated by federal agencies.”

Rai agreed.

“The NIH and FDA have been very cautious about this,” he said. “They are aware that the dangers of something going dramatically wrong are serious. We all need to proceed with caution.”

Other obstacles

Because of the significant challenges associated with creating and administering autologous T cells, some researchers predict a showdown between advancements in therapeutic agents and advancements in T-cell technology.

Grever took issue with this mindset.

“It may be perceived as a race, and some may conduct their research as though it is a race, but the fact is we need both strategies,” Grever said. “Leukemic cells will find ways around these medicines. The more weapons we have in our arsenal, the better.”

Rai agreed, but he said the key element may be chimeric antigen receptors. The development of effective chemotherapeutic agents is relatively easy compared with the development of T-cell technology, he added.

“There are not as many shortcuts in this treatment as there are in others,” he said.

Because of the complexity of the technology, Rai encouraged researchers to think broadly.

“We should consider whether the patient’s own T cells need to be used,” he said.

He acknowledged the reality of graft-versus-host disease in this scenario, but he suggested that this clinical consequence may be equivalent with the immunoregulatory- and kidney-related events associated with chimeric antigen receptors.

“If we were to have a bank of T cells that could be induced to lose their self-identity and injected into patient, we could move several steps forward,” Rai said.

Sadelain also encouraged the clinical community to examine both its successes and failures, and he noted the irony embedded in Porter’s results.

“We have gone from not even having tumor-specific T cells to administer to trying to pull back their potency to prevent the unrelenting killing of every B cell in the body,” Sadelain said. “This tells us that we have succeeded greatly, and that we have come a long way, but that significant challenges remain.” – by Rob Volansky

References:

Davila ML. Oncoimmunology. 2012;9:1-7.

Jensen MC. Biol Blood Marrow Transplant. 2010;16:1245-1256.

Kochendorfer JN. Blood. 2010;116:4099-4102.

Kochendorfer JN. Blood. 2011;119:2709-2720.

Porter DL. #717. Presented at: ASH Annual Meeting and Exposition; Dec. 8-11, 2012; Atlanta.

Porter DL. N Engl J Med. 2011;365:725-733.

Salvodo B. J Clin Invest. 2011;121:1822-1826.

For more information:

Lawrence J.N. Cooper, MD, PhD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; email: ljncooper@mdanderson.org.

Michael Grever, MD, can be reached at 395 W. 12th Ave., Columbus, OH 43210; email: grever.1@osu.edu.

Kanti R. Rai, MD, can be reached at Long Island Jewish Medical Center, 270-05 76th Ave., New Hyde Park, NY 11040; email: krai@nshs.edu.

Michel Sadelain, MD, PhD, can be reached at Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: m-sadelain@ski.mskcc.org.

Mitchell Smith, MD, PhD, can be reached at Cleveland Clinic Main Campus, Mail Code R35, 9500 Euclid Ave., Cleveland, OH 44195.

Meir Wetzler, MD, FACP, can be reached at Roswell Park Cancer Institute, Elm and Carlton streets, Buffalo, NY 14263; email: meir.wetzler@roswellpark.org.

Disclosure: Cooper, Grever, Rai, Sadelain, Smith and Wetzler report no relevant financial 
disclosures.

Do genetically modified T cells offer promise in the treatment of solid tumors?

 

Christine E. Brown

This is an exciting time for the expanded application of chimeric antigen receptor (CAR) T cells for the treatment of solid tumors.

The potential for treating solid tumors with CAR T cells builds on the successes of our group and others with targeting hematologic malignancies with CD19-specific CAR T cells, as well as approaches utilizing tumor-infiltrating and viral-specific T cells.

For the treatment of high-grade glioma, our team at City of Hope has developed an IL-13 receptor alpha-2–specific CAR T-cell platform. We have evaluated the safety and feasibility of intracranial adoptive transfer of CD8+ CAR T cells in two phase 1 clinical trials, assessing both a CAR-engineered autologous T-cell product, as well as a steroid resistant allogenic T-cell product.

Encouragingly, these studies have demonstrated the feasibility of this approach, providing evidence for transient antitumor responses for patients with IL-13 receptor alpha-2–positive glioblastoma in the absence of serious side effects.

To achieve sustained regression of solid tumors, including high-grade glioma, CAR T-cell therapy must overcome many challenges, including a highly suppressive microenvironment and a diverse antigen landscape. To address these potential barriers, strategies are being developed to further optimize CAR T cells through more potent CAR constructs expressed in T-cell populations with enhanced persistence.

Further, with respect to the challenge of tumor targeting, no dominant antigen has emerged for solid tumors that is similar to the utility of CD19 for many classes of hematologic malignancies. Thus, an additional challenge is the identification of validated targets that are broadly expressed in malignant disease, while not expressed at significant levels on critical normal tissues. Moreover, the heterogeneity of solid tumors likely will dictate that targeting single antigens will not be sufficient, and tumor eradication will require combination therapies targeting multiple antigens.

Thus, although the treatment of solid tumors does pose additional challenges for CAR T-cell therapy, promising early clinical experience indicates that efforts to overcome these obstacles are warranted. I am very optimistic for what we will be able to achieve using CAR T cells in our search for more effective therapies against solid tumors.

Christine E. Brown, PhD, is an associate research professor and associate director of the T-cell Therapeutics and Research Lab at City of Hope. She can be reached at City of Hope, 1500 E. Duarte Road, Duarte, CA 91010; email: cbrown@coh.org. Disclosure: Brown reports no relevant financial disclosures.

 

Jeffrey S. Weber

Their applicability to cancer patients with solid tumors is limited.

Adoptive cell therapy with autologous T cells derived from peripheral blood that have been genetically modified with constructs encoding T-cell receptors or chimeric antigen receptors (CAR) has been shown to induce tumor regression in patients with melanoma and B-cell malignancies.

However, their applicability to cancer patients with solid tumors is limited by the lack of well-defined tumor-specific antigens that can serve as targets.

Antigen expression shared with normal tissues may result in off-target effects. These effects may result in low levels of toxicity that are acceptable, seen with CD19, an antigen expressed in B-cell malignancies and normal B-lineage cells, which potentially can result in B-cell deficiency.

In contrast, when CARs have been used in patients to target antigens on solid tumors such as carbonic anhydrase IX7, MAGE-38 or HER-2, the toxic off-target effects may be severe and life-threatening or lethal.

It is the lack of good targets for single CARs that have a very high degree of tumor specificity that seem to limit the opportunities for successful use of the CAR technology in solid tumors. It appears that many individual solid tumor antigens are not tumor specific, but what if CAR specificity lay in recognition of multiple antigens?

To address that question, one group has devised a strategy in which a low- or moderate-affinity CAR is expressed along with a co-stimulating molecule that also recognizes a second tumor antigen. The T cells expressing the combination of constructs only recognizes tumor cells expressing both antigens, not one alone, and will not trigger cytolysis with single antigen-expressing target cells, avoiding cross reactivity with normal cells.

By using this strategy to decrease the affinity of recognition of the CAR, but maintaining specificity of targeting, severe toxicity to normal tissues may be avoided. Does this mean that the use of CARs will always be prohibitively toxic in solid tumors? No, but it gives pause and suggests that investigators in the field need to achieve better and more specific targeting of CARs, such as proposed by Sadelain and colleagues.

Jeffrey S. Weber, MD, PhD, is director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center. He can be reached at 12902 Magnolia Drive, SRB2, Tampa, FL 33612; email: jeffrey.weber@moffitt.org. Disclosure: Weber reports no relevant financial disclosures.

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