February 2015 Edition Vol.11, Issue 2

CAR-T Cell Therapies Moving Toward Clinic

CAR-T Cell Therapies Moving Toward Clinic:

An Update from ASH 2014

By Lynne Lederman, PhD

 

At this past December’s American Society of Hematology (ASH) annual meeting, abstracts as well as a special scientific symposium were devoted to CAR-T cell therapies. T cells engineered to express engineered T cell receptors or chimeric antigen receptors (CARs) targeted to tumor-associated antigens have shown promise in treating malignancies with poor prognoses. In particular, CAR-T cells against the B cell-specific antigen CD19 have been used to treat patients with B cell malignancies, including acute lymphocytic leukemia (ALL), non-Hodgkin’s lymphoma (NHL), and chronic lymphocytic leukemia (CLL) with sufficient success that the US FDA has granted breakthrough therapy designation to CAR-T cell therapies.

CTL019 Shows Clinical Efficacy

During the special scientific symposium on chimeric antigen T cell therapy, Carl H. June, MD, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, reviewed the history and the therapeutic efficacy of CAR-T cells, focusing on CTL019, produced by lentiviral transduction of an anti-CD19 CAR. CTL019 (tisagenlecleucel-T) is being co-developed by the University of Pennsylvania and Novartis Pharmaceuticals Corporation. The University of Pennsylvania is currently conducting CTL019 trials and is determining patient eligibility.

CD19 is an ideal tumor target in B cell malignancy because CD19 expression is generally restricted to B cells and B cell precursors with no expression on hematopoietic stem cells. CTL019 is a second-generation CAR-T cell that combines an extracellular anti-CD19 antibody fragment with costimulatory intracellular signaling domains, CD3-zeta and CD137 (4-1BB).

Notable CTL019 toxicities include B cell aplasia in all responding patients, which is managed with intravenous immunoglobulin replacement. Cytokine release syndrome (CRS), which is correlated with disease burden, can be managed with anti-IL6 therapy (tocilizumab).

Stephan A. Grupp, MD, PhD, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, updated results of a pilot phase 1/2a study of CTL019 in children with ALL1 (funded by Novartis).

Complete remissions (CR) were seen in 36 of 39 (92%) of pediatric patients with ALL treated with CTL019 at 1 month; and 25 of the 36 (69%) remained in remission at a median follow-up of 6 months. All responding patients experienced CRS, which was severe and required treatment in a third of responding patients. Macrophage activation syndrome and neurotoxicity were reported in a few patients. Of 10 patients experiencing relapse (5 due to loss of CAR-T cells, 5 due to loss of CD19-positive target cells), 5 died. Responses appear to be durable, with CAR-T cells persisting for at least 2 years in patients with continued responses. All responders had B cell aplasia. Phase 2 trials are ongoing.

During the special scientific symposium on chimeric antigen T cell therapy, Steven A. Rosenberg, MD, PhD, Chief, Surgery Branch, National Cancer Institute, Bethesda, Maryland, discussed the possibility of using cell transfer therapy for solid tumors. Unlike many hematologic malignancies, the lack of common targets in solid tumors represents a major obstacle to progress. He commented that the loss of normal B cells in patients treated with CD19 CAR-T cell therapy is “the price you pay” for the therapy, given the presence of the CD19 antigen on normal B cells as well as B cell-derived malignancies.

In partnership with the NCI Surgery Branch through a Cooperative Research and Development Agreement (CRADA), Kite Pharma, Inc., Santa Monica, California, plans to conduct trials of gamma retrovirally transduced CAR-T cells targeting CD19 (KTE-C19) for the treatment of diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma, ALL, and CLL.

Sleeping Beauty Gene Approach

A non-viral technique for creating CD-19 CAR-T cells is the so-called “Sleeping Beauty” (SB) gene transfer system, developed at the University of Minnesota and currently used at the University of Texas MD Anderson Cancer Center to treat patients with ALL, NHL, or CLL in clinical trials. The SB gene “awakens” a transposon in a plasmid that also contains the therapeutic gene to be transferred; the SB transposon in one plasmid is transferred along with a second plasmid coding for hyperactive SB transposase; the transposon and gene are inserted by the transposase into the target DNA sequence. Partow Kebriaei, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, presented results of current trials.2

Second generation CD19-specific CAR patient or allogeneic donor-derived T cells were generated for 42 patients with advanced B cell malignancies: ALL (n=19), NHL (n=17), or CLL (n=5), and administered in the adjuvant setting after autologous (n=5), allogeneic (n=21), or umbilical cord (n=4) hematopoietic cell transplantation (HCT), or for the treatment of active disease (n=12). Of 5 patients at high risk of relapse treated with CAR-T along with autologous stem cell transplants, 4 remain in CR at a median follow-up of 12 months. Of 13 patients treated with donor CAR-T cells after allogeneic stem cell transplantation, 6 remain in CR with a median follow-up of 7.5 months. Of 14 patients treated with CAR-T cells alone, 5 have experienced disease regression with a median follow-up of 6 months.

No acute or late toxicities have been seen. Two patients who were treated with allogeneic CAR-T cells from allogeneic transplant donors developed acute graft versus host disease, an expected complication following transplant.

Dr. Kebriaei speculated that because the gene transfer is non-viral, the SB system might face fewer regulatory obstacles. Future plans include modifying the product to improve in vivo proliferation and persistence. “Ultimately, the goal of these therapeutics, regardless of the route of transduction, is to develop an off-the-shelf product that would be readily available to the patient,” she said. Also noting that although she had no idea what the cost of therapy might be, the “hope is that when these therapies get commercialized and mass manufacturing is more efficient, they will be relatively affordable, and available to all patients,” rather than maintain their current “boutique” state.

Juno’s CAR-T Cell Therapy Also Promising

Jae H. Park, MD, Memorial Sloan Kettering Cancer Center, New York, New York, presented results of the phase 1 trial of JCAR015 in adults with ALL.3 JCAR015 is a second generation CD19 targeting CAR-T cell therapy, one of several developed by Juno Therapeutics, Seattle, Washington. T cells are transduced with a retrovirus encoding a CAR construct of anti-CD19 single chain FV region linked to signaling domains, including the costimulatory CD28 domain.

Of 27 evaluable adult patients enrolled with relapsed, refractory B-ALL, 24 (89%) had CR, and 21/24 (88%) had complete molecular remission. Median overall survival was 8.5 months. Patients with and without subsequent allogeneic stem cell transplant had durable responses.

As in the CTL019 trials, CRS occurred in 5 of 15 patients with high disease burden, requiring vasopressors and/or mechanical ventilation, and did not occur in any of 13 patients without morphologic disease. Grade 3 or 4 neurotoxicity occurred in 7/28 patients and was generally reversible. IL-6 levels may be involved in the neurologic toxicity and the effect of early intervention with IL-6-targeted treatment will be investigated.

JCAR015 was also investigated in a phase 1 trial in patients with poor-risk B-cell NHL.4 Craig S. Sauter, MD, Memorial Sloan Kettering Cancer Center, New York, New York, presented the interim analysis. At a median follow-up of 9 months, all 6 patients were alive, although one patient experienced severe CRS.

Phase I clinical trial results of JCAR014 in patients with relapsed, refractory B cell malignancies, were presented by Cameron J. Turtle, MBBS, PhD, Fred Hutchinson Cancer Research Center, Seattle, Washington.5 Numbers of patients were small; complete molecular remissions occurred in 9/11 (82%) patients with ALL and in both patients with CLL.

Severe CRS was observed in 3 of 13 (23%) patients with ALL, including one death; CRS was not observed in patients with CLL or NHL.

Looking Ahead

Several obstacles lie in CAR-T cell therapy’s path to the clinic. At this time, all therapies rely on collecting a patient’s T cells, modifying them, then re-infusing them, a labor-intensive process requiring some lag time between T cell collection and treatment. Production of patient-specific CAR-T therapies is likely to be extraordinarily expensive.

Before this promising therapeutic approach reaches the clinic, ways to manage the associated potentially fatal adverse events, such as cytokine release syndrome (cytokine storm) need to be perfected. However, these events will be weighed against the side effects of current therapies for CAR-T cell-targeted diseases; bone marrow transplant and chemotherapy to treat central nervous system involvement have their own morbidities and mortalities.

Finally, long-term follow-up of patients as clinical trials progress will show whether CAR-T therapy can provide at least some patients with poor prognosis disease with a cure.

References

  1. Grupp SA, et al. Cells Engineered with a Chimeric Antigen Receptor (CAR) Targeting CD19 (CTL019) Have Long Term Persistence and Induce Durable Remissions in Children with Relapsed, Refractory ALL. Blood. 2014;124 (21) Abstract 380.
  2. Kebriaei P, et al. Adoptive Therapy Using Sleeping Beauty Gene Transfer System and Artificial Antigen Presenting Cells to Manufacture T Cells Expressing CD19-Specific Chimeric Antigen Receptor. Blood. 2014;124 (21) Abstract 703.
  3. Park JH, et al. CD19-Targeted 19-28z CAR Modified Autologous T Cells Induce High Rates of Complete Remission and Durable Responses in Adult Patients with Relapsed, Refractory B-Cell ALL. Blood. 2014;124 (21) Abstract 382.
  4. Sauter CS, et al. Interim Safety Analysis: a Phase I Trial of High Dose Therapy and Autologous Stem Cell Transplantation Followed By Infusion of Chimeric Antigen Receptor Modified T-Cells (19-28z CAR-T) Directed Against CD19+ B-Cells for Relapsed and Refractory Aggressive B Cell Non-Hodgkin Lymphoma (B-NHL). Blood. 2014; 124 (21) Abstract 677.
  5. Turtle CJ, et al. Therapy of B Cell Malignancies with CD19-Specific Chimeric Antigen Receptor-Modified T Cells of Defined Subset Composition. Blood. 2014;124 (21) Abstract 384.

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