COMMENTARY

CAR T-Cell Therapy at ASH 2015: What's Hot

Miguel-Angel Perales, MD

Disclosures

December 01, 2015

The 2015 annual meeting of the American Society of Hematology (ASH) is just around the corner, and it's time to preview what to expect from "Detroit's Big 3"—Juno Therapeutics, Kite Pharma, and Novartis—as well as some of the new kids on the block. As has been the case at ASH the past couple of years, I expect immunotherapy and chimeric antigen receptor (CAR) T cells in particular to make a big splash again; and below I will outline some of the abstracts that caught my attention.

In fact, CAR T cells have recently been in the news yet again, even before some of us booked our flights. A report from Great Ormond Street Hospital in London that was widely covered in the press describes a young child with relapsed acute lymphocytic leukemia (ALL) who was treated with "gene-edited" CD19 CAR T cells (UCART19), based on technology being developed by Cellectis. Using TALEN [transcription activator-like effector nucleases] gene-editing technology, the investigators were able to use third-party T cells where the TCR-alpha gene was knocked out to prevent the risk for graft-vs-host disease, and the CD52 gene was knocked out to make the cells resistant to alemtuzumab. In addition, the T cells included an off-switch by being engineered to express the RQR8 marker/suicide gene, which renders the cells sensitive to rituximab. This case is the first-in-human report of CAR T cells that make use of gene editing.

Although it is somewhat difficult to determine the exact effect of the cells from the press release, and given the fact that the patient underwent a second transplant, it will be interesting to see the details of this work presented at ASH (abstract 2046).

Of note, Novartis announced earlier this year that it was investing in California-based Caribou Biosciences, an early-stage biotech developing CRISPR [clustered, regularly interspaced, short palindromic repeats]-Cas9 gene-editing technology. Another recent study worth mentioning was the report by Rapoport and colleagues[1] in Nature Medicine describing the use of NY-ESO-1 TCR engineered T cells in patients with multiple myeloma. Clinical responses were seen in 16 of 20 patients (80%).

Focusing on this year's ASH annual meeting, we can hit the road with a session on "Harnessing T Cells in Therapy of Hematologic Malignancy" that is part of the scientific program. This session will include talks by three leading investigators in the field: Dirk Busch, MD, from the Technische Universitat Munchen in Munich, Germany, will talk about the "Choice of Better T-cells for Adoptive Immunotherapy"; Michel Sadelain, MD, PhD, from Memorial Sloan Kettering Cancer Center in New York, New York, will give a talk titled, "From T-cell Engineering to CAR therapy: Progress and Prospects"; and Crystal Mackall, MD, from the National Institutes of Health/National Cancer Institute in Bethesda, Maryland, will discuss the "Latest in Clinical Application of CAR Cell Therapy for B-cell Malignancy and Transplantation."

Beyond these sessions, a quick search of the program reveals around 100 abstracts on the topic of chimeric antigen receptors. Stephan Grupp, MD, PhD, from Children's Hospital of Philadelphia, will provide an update in 53 children and young adults with ALL treated with CTL019 and achieving a 94% complete remission (CR) rate (abstract 681). Twenty of the patients with a CR subsequently relapsed, including 13 with CD19(-) blasts, indicating a common mechanism of resistance. Stephen Schuster, MD, of the University of Pennsylvania, will give an update on the results of CTL019 in patients with lymphoma. Rounding out the studies supported by Novartis, Shannon Maude, MD, PhD, from Children's Hospital of Philadelphia, will describe her experience in five children who received a second infusion of CTL019 for B-cell recovery (n=3) or CD19+ relapse (n=2; abstract 683). Three patients showed no response and progressed (n=1) or relapsed with CD19+ (n=1) or CD19- (n=1) ALL. She also reports the first use of humanized anti-CD19 CAR T cells (CTL119), which induced a remission in a patient with ALL refractory to prior CD19-directed murine CAR T-cell therapy. Jennifer Brudno, MD, of the National Cancer Institute, will report results of allogeneic CAR T cells after allogeneic hematopoietic stem cell transplantation (HSCT) and show remissions in 8 of 20 patients, including six CR and two partial remissions (abstract 99). Along these lines, the group from MD Andersen Cancer Center will also report results of donor-derived CAR T cells given as pre-emptive treatment after allogeneic HSCT (abstract 862). The group at Memorial Sloan Kettering Cancer Center presented clinical updates in ALL and non-Hodgkin lymphoma (NHL) at the American Society of Clinical Oncology meeting earlier this year. At ASH, Jae Park, MD, of Memorial Sloan Kettering Cancer Center, will report results in 44 patients with ALL treated with 19-28z CAR T cells and show that posttreatment minimal residual disease (MRD) status is predictive of overall survival: 76% (95% confidence interval [CI]: 51-89) in MRD- CR vs 14% (95% CI: 8-45) in MRD+ CR cohort (abstract 682).

In a paper from the "West Coast branch of Juno," Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, will report results in NHL patients using defined populations of CD19 CAR T cells and show higher CR rates with fludarabine/cyclophosphamide vs cyclophosphamide-alone lymphodepletion (abstract 184). Finally, a few other preclinical studies worth mentioning are abstracts 383 and 852.

This is just a quick sample of the studies that will be at ASH this year. For some additional background information, check out our recently published review on CAR T cells and checkpoint inhibitors[2] or the November/December issue of The Cancer Journal, a special issue on cell transfer therapy for cancer.

Sessions

Harnessing T Cells in Therapy of Hematologic Malignancy
Saturday, December 5, 2015: 7:30 AM-9:00 AM, W304, Level 3 and Sunday, December 6, 2015: 9:30 AM-11:00 AM, W304, Level 3.

Abstracts

Abstract 99: Allogeneic T-Cells Expressing an Anti-CD19 Chimeric Antigen Receptor Cause Remissions of B-Cell Malignancies after Allogeneic Hematopoietic Stem Cell Transplantation without Causing Graft-Versus-Host Disease

Abstract 183: Sustained Remissions Following Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) in Patients with Relapsed or Refractory CD19+ Lymphomas

Abstract 184: Anti-CD19 Chimeric Antigen Receptor-Modified T Cell Therapy for B Cell Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: Fludarabine and Cyclophosphamide Lymphodepletion Improves In Vivo Expansion and Persistence of CAR-T Cells and Clinical Outcomes

Abstract 383: Myeloid Cells in Peripheral Blood Mononuclear Cell (PMBC) Concentrates Inhibit the Expansion of Chimeric Antigen Receptor (CAR) T Cells

Abstract 681: Durable Remissions in Children with Relapsed/Refractory ALL Treated with T Cells Engineered with a CD19-Targeted Chimeric Antigen Receptor (CTL019)

Abstract 682: Implications of Minimal Residual Disease Negative Complete Remission (MRD-CR) and Allogeneic Stem Cell Transplant on Safety and Clinical Outcome of CD19-Targeted 19-28z CAR Modified T Cells in Adult Patients with Relapsed, Refractory B-Cell ALL

Abstract 683: Efficacy and Safety of Humanized Chimeric Antigen Receptor (CAR)-Modified T Cells Targeting CD19 in Children with Relapsed/ Refractory ALL

Abstract 852: Identification of PD1 and TIM3 As Checkpoints That Limit Chimeric Antigen Receptor T Cell Efficacy in Leukemia

Abstract 862: Pre-Emptive Donor Lymphocyte Infusion with CD19-Directed, CAR-Modified T Cells Infused after Allogeneic Hematopoietic Cell Transplantation for Patients with Advanced CD19+ Malignancies

Abstract 2046: First Clinical Application of Talen Engineered Universal CAR19 T Cells in B-ALL

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