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Insight & Intelligence™: Apr 22, 2015

AACR Special: Serial Killer Cells on the Side of the Angels

Researchers Discuss Strategies to Improve the Safety and Effectiveness of Reengineered T cells in Eradicating Tumors

AACR Special: Serial Killer Cells on the Side of the Angels

Scanning electron micrograph of a human T cell from the immune system of a healthy donor. [National Institute of Allergy and Infectious Diseases]

    Persistent, repeated “kills” seem less and less of a problem for reengineered T cells. Such cells, whether they are chimeric antigen receptor (CAR) T cells or antigen-specific T-cell receptor (TCR) T cells, not only persist in the body after they have been infused, they make a habit of slaying tumors. It is not unusual for one reengineered cell T cell to dispatch as many as 1,000 tumor cells over the length of its career.

    Yet, to judge by an adoptive T-cell therapy symposium organized by the American Association for Cancer Research (AACR), there is still concern that reengineered T cells might become indiscriminate killers. This symposium, held April 21, definitely focused on killer cells that are made, and not those that are recruited, namely, tumor-infiltrating lymphocytes (TILs). And, if attendee questions were any indication, the toxicity of “made” killer cells is very much a concern.

    CAR T cell and TCR T cell toxicities, the speakers acknowledged, can be hard to predict. Yet these cells remain an attractive alternative to TILs. CAR T cells and TCR T cells are more manufactured than cultivated, and so they can be produced in quantity and in relatively short order. Timely manufacture could help reengineered T cells defeat a cancer before a patient succumbs to illness. Also, reengineered T cells may turn out to be useful against cancers that may continue to elude TILs.

    The speakers that discussed reengineered T cells included Carl H. June, M.D., of the Abramson Cancer Center of the University of Pennsylvania; Michel Sadelain, M.D., Ph.D., of the Memorial Sloan Kettering Cancer Center; and Philip D. Greenberg, M.D., of the Fred Hutchinson Cancer Research Center and the University of Washington.

    Dr. June’s presentation—“TCR-engineered T cells: Can they catch CARS?”—not only weighed TCR approaches against CAR approaches, it also considered enhanced TCR and CAR T cell approaches. These approaches were also referenced other AACR presentations to which Dr. June contributed.

    In one of these presentations, the authors hypothesized that infusion of genetically modified tumor-specific T cells following autologous stem cell transplant (ASCT) may overcome various barriers in treating multiple myeloma (MM). These barriers include antigen specificity, low levels of target expression, and failure to break self-tolerance.

    “[Our] data show that NY-ESOc259-T cells exhibit robust trafficking and expansion, durable persistence without exhaustion, and follow a natural immune expansion and contraction pattern consistent with an antigen-driven mechanism of action,” the authors indicated. “Relapse correlated with a loss of persistence or tumor antigen escape, suggesting that targeting multiple antigens and maintenance infusions may increase durable remissions.”

    Another presentation made the case that TCR-engineered adoptive T-cell therapy for lung cancer can be augmented by combined PD1 and TIM3 antibody blockade: “The PD1 and TIM3 pathways are involved in tumor-induced hypofunction of TCR-engineered TILs. Combining anti-hPD1 and anti-hTIM3 antibodies with TCR T cells, and likely CAR T cells, will likely enhance the efficacy of these approaches in lung cancer and other solid tumors.”

    CAR T cells also figured in Dr. Sadelain’s presentation, which was entitled, “CARs—From assembly to distribution.” Better CAR assembly, said Dr. Sadelain, could be accomplished with third-generation constructs. Examples provided by Dr. Sadelain combined CD28 and 41BB middle domains for enhanced signaling.

    Improved delivery, experiments with rodents suggest, may be a matter of relying on intrapleural rather than intravenous administration. Intrapleural bested intravenous delivery in potentiating CAR T cell efficacy.

    But what of safety? In the breach, said Dr. Sadelain, it would be possible to install a “suicide gene,” as was done in the rodent studies. Also, one could carefully escalate the doses of reengineered T cells, the better to lessen the severity of the cytokine release syndrome. In general, said Dr. Sadelain, the higher the patient’s tumor burden, the greater the cytokine storm’s severity. Nonetheless, he added, it should be possible to calibrate the dosing to account for tumor burden, and thereby reduce cytokine-related toxicity.

    Attention swung back to TCRs in the next presentation—“Employing TCRs in engineered T cells to develop therapeutic reagents for effectively targeting malignancies.” This presentation, delivered by Dr. Greenberg, described the identification of candidate antigens in a model of leukemia.

    Dr. Greenberg’s team focused on WT1, a gene known to be associated with promoting leukemic transformation. After the team showed that WT1 is expressed in comparative abundance in human leukemic stem cells, they explored its safety and efficacy in preclinical trials, as well as in an initial clinical trial with poor-prognosis leukemia patients.

    “This study demonstrated that [WT1-specific CD8 T cell clones] were safe, mediated in vivo anti-leukemic activity, and were associated with maintenance of long-term remissions in some patients,” reported Dr. Greenberg’s team. These investigators, however, realized that generating sufficient numbers of WT1-specific CD8 T cells with high avidity for the target in each patient represented a “substantive problem.”

    Dr. Greenberg then mentioned the methods his team used to genetically engineer patient T cells to acquire high avidity for the tumor target. Yet other problems remain.

    “Unfortunately, providing a high-avidity T-cell response does not necessarily result in tumor eradication, as there are other substantive obstacles that can preclude even a T cell expressing a high-affinity TCR from being effective,” explained Dr. Greenberg and colleagues. “These impediments include the development of T-cell dysfunction, particularly within the microenvironment of solid tumors, and we are using genetically engineered mouse models to elucidate the cellular and molecular pathways that need to be modulated to achieve meaningful therapeutic benefit in a variety of solid tumor settings, including pancreatic and ovarian cancer.”

    According to Dr. Greenberg, means of achieving better infiltration are being explored in preclinical models. Already, the insights gained could lead to clinical trials in the next couple of years.

    “[Our] models,” assert Dr. Greenberg and colleagues, “have helped elucidate the importance of not only cell-extrinsic mechanisms of regulation and dysfunction that render T cells unresponsive … but also the cell-intrinsic mechanisms that derive in large part from persistent stimulation by the tumor antigen and ultimately can render T cells progressively dysfunctional.” These cell-intrinsic mechanisms can lead to epigenetic modifications that eventually result in nonresponsive cells that cannot be readily rescued.

    To sustain T-cell function and antitumor activity, Dr. Greenberg’s team hopes to use genetically modified T cells that can not only disrupt inhibitory pathways, but do so more selectively than systemically administered monoclonal antibodies or cytokines.

    “As different tumor types exhibit unique characteristics and are capable of engaging distinct inhibitory pathways, improved understanding of the immunobiology of the tumor type to be treated will likely prove essential,” Dr. Greenberg’s team concludes. “However, the relatively straightforward means to use synthetic biology to genetically engineer T cells to acquire novel capacities to overcome inhibitory signals and function in the tumor microenvironment suggests that cancer therapy with engineered T cells will likely find an increasing role in the treatment of human cancers.”

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