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CAR-T Cells: The Next Era in Immuno-Oncology
Bruce A. Feinberg, DO; Jennifer Fillman, MBA; Justin Simoncini, MBA, MPH; and Chadi Nabhan, MD, MBA, FACP
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CAR-T Cells: The Next Era in Immuno-Oncology

Bruce A. Feinberg, DO; Jennifer Fillman, MBA; Justin Simoncini, MBA, MPH; and Chadi Nabhan, MD, MBA, FACP
An update on immunotherapies and the potential impact of chimeric antigen receptor (CAR)-T cells on oncology care.
Early Clinical Experience: Efficacy

In Table 1, we have summarized selective data from completed or ongoing phase I/II CAR-T trials, which have been published and presented. This early research has focused on cancers in which the malignant cells express CD19—an antigen expressed only on malignant and normal B cells. CAR-T cells expressing anti-CD19 recognize and kill CD19-expressing malignant cells.10 Among the CD19-expressing malignancies, pediatric R/R ALL has garnered the most attention. CAR-T treatment of pediatric R/R ALL has resulted in remarkable clinical benefit and fewer severe adverse events (SAEs) than adult R/R ALL treated with CAR-T cells, making pediatric ALL the leading candidate for the first FDA-approved indication.

Stakeholder adoption will likely be brisk for the same reasons, but the overall healthcare impact might be limited given the nature of this disease and the relatively small number of eligible patients; 2500 to 3500 new pediatric ALL in the United States are diagnosed annually, 80% of which are of B-cell lineage (CD19-positive); current 5-year survival is 85%, and treatment-related mortality is 1% to 3%.11 While responses are attained with blinatumomab in the small number of R/R patients, they are rarely durable and less than one-third of pediatric patients with R/R ALL are cured with allogeneic HSCT.11,12

Analogous to ALL, other CD19-expressing hematologic malignancies have been targeted with CAR-T cells. While the CAR-T cells used in these studies target anti-CD19, they are not all identical. The methodology to develop the fusion protein that makes a CAR T is unique to each manufacturer and represents 1 variable that may be responsible for differing efficacy and toxicity outcomes. The U-Penn group reported an overall response rate (ORR) of 57% (complete response [CR], 29%) in a cohort of patients with R/R chronic lymphocytic leukemia (CLL).13

The National Cancer Institute (NCI) reported on 15 patients: 9 with R/R diffuse large B-cell lymphoma (DLBCL), 2 with R/R indolent lymphoma, and 4 with R/R CLL.14 Of the entire NCI cohort of 15 patients, 8 achieved CRs; 4, partial remissions (PRs); and 1, stable disease. Investigators at the Fred Hutchinson Cancer Research Center (FHCRC) reported on 34 R/R non-Hodgkin lymphoma (NHL) patients, 18 of whom had DLBCL; 6, follicular lymphoma (FL); 6, CLL; and 4, mantle cell lymphoma (MCL).15 CRs in studied subtypes were: 38% in DLBCL, 67% in FL, and 50% in CLL.

Another study by the U-Penn group included 38 R/R patients who had either FL (14), DLBCL (21), or MCL (3).16 The median number of prior therapies was 4 (range: 1-10) and 32% of patients had prior autologous HSCT. ORR among 22 evaluable patients at 3 months was 54% in DLBCL, 100% in FL, and 50% in MCL. The 3-month ORR was 54% in DLBCL, 100% in FL, and 50% in MCL.16 The ZUMA-1 study confirmed multi-center CAR-T treatment feasibility, with the following reported results on 51 relapsed/refractory DLBCL patients treated with KTE019; Orr was 76% with CR in 47%.17 Finally, preliminary data also support activity in myeloma where studies are ongoing to explore how this strategy is best positioned among other recently approved novel antimyeloma agents.18

A critical component of the CAR-T treatment is the preinfusion conditioning regimen to reduce the circulating and competing T-cell population. Conditioning regimens varied in published studies suggesting that the conditioning program could be another factor impacting differential efficacy and toxicity. It is becoming increasingly clear that the selection of the conditioning program will be essential to optimize clinical outcomes, especially SAEs. Some patients in the trials presented were treated with fludarabine plus cyclophosphamide conditioning, while others received cyclophosphamide monotherapy. In one study, the combination regimen resulted in a higher CR (42% versus 8%), positioning it as a benchmark, if not a standard, in this nascent field of research.15

Early Clinical Experience: Toxicity

The rapidity with which CAR-T treatment has become the standard of care in pediatric R/R ALL, as well as expanded indications across R/R B-cell CD19–expressing malignancies—such as CLL, DLBCL, MCL, and others—may have more to do with managing SAEs than with efficacy. The SAE that has garnered the most attention is cytokine release syndrome (CRS) because it is the most dangerous toxicity, usually occurring shortly after infusion although it can be delayed up to 3 weeks after.26 Cytokines are immune cell signaling proteins that we associate with flu-like symptoms, which, if released into the circulation rapidly and in large amounts (cytokine storm), can be physiologically overwhelming and lead to vascular collapse and possible death.26

Grading of CRS toxicity has not been uniformly agreed upon. Severe CRS occurred in 7/16 (44%) patients in the Memorial Sloan Kettering Cancer Center (MSKCC) trial, 8/30 (27%) at U-Penn, 6/21 (29%) at the NCI, and 7/30 (23%) at FHCRC.27 Deaths attributed to CRS have been suggested in only 2 out of 97 pediatric patients with R/R ALL (2%). The Juno Rocket trial has been held twice by the FDA due to SAE-related deaths, albeit not necessarily CRS-related. Observations that CRS may be mediated by IL-6 led to tocilizumab (Genentech anti–IL-6) and etanercept (anti–TNF) use.26 IL-6 rescue appears to be an intriguing strategy to manage CRS, but its standardization and overall impact on treatment remains to be determined as patients who do not have CRS are unlikely to respond. The strongest predicting factor to developing severe CRS is the leukemia burden.26 Guidelines are being developed to manage CRS—most require that C-reactive protein (CRP) be monitored daily to identify patients becoming at risk, while tocilizumab and/or steroids are recommended for high-risk patients.26

Fevers, hypotension, and a variety of neurological symptoms (confusion, obtundation, myoclonus, and aphasia) have been frequently reported, as have fatigue, diaphoresis, anorexia, and diarrhea. Neurotoxicity deserves special mention, as it is a potentially lethal toxicity and appears unrelated to CRS. Neurotoxicity, its prevention, and its relationship to tumor response are not well understood. Tumor response is clearly the basis for tumor lysis syndrome, which can occur even 3 weeks following infusion; it was noted as late as day 22 in a CLL patient in the first published CAR-T report.10 The research into predictability, prevention, and management of SAEs without abrogating the clinical benefit of CAR-T therapy will be a critical element to the success of this I-O intervention.

An Expanding Therapeutic Platform

Although the salvage therapy of B-cell malignancies may become the earliest FDA-approved indications for CAR-T therapy, long term commercial success will require broader disease indications and labeling for use at earlier stages of disease. Methodologically, chimeric fusion protein design against antigens other than CD19, is not a limitation, nor do such antigens need to be associated with blood cells. A review of the active and accruing clinical trials provides insight into this possibility. Of the 57,889 oncology trials listed on ClinicalTrials.gov, 777 matched for checkpoint inhibitors and 121 matched for CAR T. Of these 121 CAR-T trials, 58 are being conducted in China. Of the remaining 63 trials conducted in the United States and/or the European Union, 39 are phase 1, 14 are phase 1/2 hybrid, and 5 trials are phase 2; the phase is not identified for the remaining 5 (Table 2). The phase 2 trials all focus on hematologic malignancies expressing CD19. Of the 40 trials with a projected completion date before 2019, the CAR-T platform is being tested in melanoma, sarcoma, ovarian cancer, and brain tumors based on targetable antigens other than CD19. Of particular note are 6 trials involving brain malignancy, specifically glioblastoma multiforme, a disease with limited therapeutic progress over the preceding 30 years and for which CAR-T success could lead to a fast-track FDA approval and a frontline indication.



 
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