Regulatory challenges and considerations for the clinical application of CAR-T cell anti-cancer therapy

KEYWORDS:

• Immunotherapy
• adoptive T cell therapy
• chimeric antigen receptor
• gene therapy
• B cell acute lymphoblastic leukemia
• diffuse large B cell lymphoma

1. Introduction

The adoptive transfer of T cells gene-targeted with chimeric antigen receptors (CARs) has emerged as an exciting cancer immunotherapy due to the induction of complete remissions (CRs) in patients with chemotherapy-refractory hematologic malignancies. The CAR is an antigen-receptor created by fusion of the antigen-receptor domain of an antibody to the activation and co-stimulatory proteins associated with the T cell receptor (TCR) complex (reviewed in [1–3]). The CAR class most commonly investigated in clinical trials, CD19-targeted CAR T cells, will be considered for US Food and Drug Administration (FDA) approval as a standard of care for patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and diffuse large B cell lymphoma (DLBCL) in 2017 [4–9]. Such a paradigm-shifting and novel cancer therapy that relies on viral production, genetic-modification, cell expansion, quality control/quality analysis, as well as clinical application and toxicity management poses significant challenges to regulatory oversight. Institutional and federal regulatory management of CAR T cell clinical trials has proven adept at evaluating safety implications for patients. In 2016, there were at least 10 active clinical trials in the United States evaluating virally-modified CD19-targeted CAR T cell for B cell malignancies [10]. With impending approval for CD19-targeted CAR T cells, the challenges facing regulatory oversight of these products post-approval will be highlighted. The experiences with CD19-targetd CAR T cells will also serve as a valuable model to be used for cell therapies in future years.

2. Regulatory challenges

CD19-targeted CAR T cell products for pediatric B-ALL and relapsed DLBCL, life-threatening conditions, were tested in clinical trials indicating they may be more effective than existing therapies [5,8]. As such, these products were granted breakthrough therapy designation (Table 1), which allows for a rolling review with intensive guidance and organizational commitment from the FDA [11]. While this designation does not guarantee a priority review of the Biological License Application (BLA), it is intended to expedite drug development and review by the FDA and conveys all of the fast track program features [11].

Table 1. CD19-targeted CAR T cell trials with a breakthrough designation for B cell malignancies.

Agent	Breakthrough designation	Company/trial name	n	CR	Severe CRS/neurotoxicity	Ref
CTL019 (tisagenlecluecel-T)	R/R B-ALL	Novartis/ELIANA	34	83%	45%/21%	[12]
JCAR015^a	R/R B-ALL	Juno/ROCKET	NA	NA	At least five fatal neurologic toxicities	[13]
KTE-C19 (axicabtagene ciloleucel)	R/R DLBCL	Kite/Zuma01	101	39%	13%/28%	[9]

^aThis trial and the development of this product has been discontinued due to neurologic toxicities.

R/R: relapsed/refractory; NA: not available; n: number of patients; Ref: references.

If granted FDA approval these would be the first gene-modified viable cellular immunotherapy approved for the treatment of cancer. However, accelerated approval will rely on surrogate endpoint, such as response rate, in the pivotal trials. Therefore, provisional approval for these therapies, which could impact up to 10,000 patients in the US every year, will be based on no more than 200–300 patients and include only historical cohorts for comparisons. Confirmatory clinical trials and post-marketing surveillance will be required to define the morbidity, mortality, and efficacy of CD19-targeted CAR T cells for B-ALL and DLBCL and how they impact overall survival (OS) compared to standard salvage therapy. Also, the FDA may require manufacturers to maintain a Risk Evaluation and Mitigation Strategy (REMS) to ensure benefits of CAR T cell therapy outweigh risks.

Close attention will be given to cytokine release syndrome (CRS) and neurologic toxicities to define the morbidity and mortality rate of CD19-targeted CAR T cells and how it may reduce OS (Table 1). This is underscored by unexpected deaths due to cerebral edema that led to the discontinuation of the development of one CD19-targeted CAR T cell product (clinicaltrials.gov #NCT02535364). While the reasons for the discrepancy in treatment related deaths with that CAR product remains unknown, interim trial results with other CAR products suggest an acceptable risk-reward ratio can be achieved [7,14]. The production failure rate of autologous CAR T cells should also be evaluated because the cells are collected, gene-targeted, expanded, and qualified for each patient. Considering the initial approvals will be in patients with poor survival there will be limited time for collection and production before complications of refractory disease develop. Furthermore, since one of the products uses lentivirus to modify autologous T cells and the other uses gammaretrovirus they could markedly differ in regards to production failure rates, which might ultimately impact OS on an intention to treat basis.

The Center for Biologics Evaluation and Research (CBER) of the FDA regulates cellular therapy products and human gene therapy products. As the number of clinical trials in this field are increasing, and the number of products are approved, there will be a need for additional oversight tailored for the CAR T cell field. For example, there was early concern if gammaretroviral modification of T cells could lead to insertional T cell leukemogenesis such as reported in pediatric patients treated by gammaretroviral modification of stem cells [15]. Fortunately, this has not been reported in the first few hundred patients treated with CD19-targeted CAR T cells. But as the number of patients treated can reach up to 10,000 in the United States every year, rare events could occur. There needs to be a mechanism to rapidly identify these patients and evaluate rare, but potentially severe toxicities. Furthermore, there should be guidance regarding how CAR T cells are produced, infused, and toxicities managed so these advanced guidelines can be disseminated to all treatment sites.

Given the significant risk of toxicities [4,9,16], centers with experience in managing CRS and neurologic complications will likely be the first to administer these therapies after FDA approval. After roll out of the therapy to academic medical centers that participated in the development phase, additional centers with active hematopoietic stem cell transplant programs will likely be next to begin administering CAR T cells. Foundation for the Accreditation of Cellular Therapy (FACT) and Joint Accreditation Committee ISCT – EBMT (JACIE) are professional entities already in place for voluntary monitoring and accreditation of hematopoietic stem cell transplant programs. They recently published joint international standards for immune effector cell therapies, which include CAR T cell therapies [17]. This includes standards for the clinical program, collection facility, and processing facility at centers administering immune effector cells for therapeutic intent. In fact, to become FACT re-accredited upon renewal inspection, hematopoietic stem cell transplantation programs that administer CAR T cell therapy will be required to comply with these new immune effector standards. While such accreditation may not be required to administer CAR T cells, it will provide patients, payers, and manufacturers assurances that a certain level of detail and process is in place at centers delivering these therapies.

While the FDA may maintain oversight utilizing a REMS program long term follow-up of outcomes and maintenance of biological samples may be required of manufacturers. Such databases and repositories might be contracted out to existing entities. For example, the Stem Cell Acts of 2005, 2010, and 2015 are managed by HRSA of the U.S. Department of HHS. The Stem Cell Acts include the C.W. Bill Young Cell Transplantation Program, which established an outcomes database, and The Stem Cell Therapeutic Outcomes Database (SCTOD), which collects data and performs research. The SCTOD component is administered by the Center for International Blood and Marrow Transplant Research (CIBMTR), which collects data from centers administering autologous and allogeneic blood cell therapies. Similar arrangements for CAR T cells monitoring will also be useful, whether the manufacturers, CIBMT, or another third party do the work.

An additional area of regulation concerns reimbursement. Private insurers should offer the therapy based upon significant clinical improvements over standard of care and we expect that manufactures and payers will drive administration toward centers with expertise following a ‘center of excellence’ model. However, both the cell therapy product and the highly specialized medical care needed to safely administer the therapy will not come without cost. The Centers for Medicare and Medicaid serves (CMS) typically sets prices for therapies administered in the inpatient setting by Diagnosis-Related Group (DRG) for Medicare reimbursement. Payment for care delivery would be left to reimbursement for associated costs on existing DRGs until new classifications and coding can be developed, a process that will take time. One way to accelerate appropriate reimbursements to providers is via the New Technology Add on Payment (NTAP) program. An NTAP may be granted by CMS in cases where the technology is new, existing DRG payments for the service are inadequate, and the technology offers a substantial clinical improvement over existing services [18].

3. Expert opinion

There has been significant progress in the clinical development of CAR T cell therapy to treat B cell malignancies. Regulatory challenges abound as this is the first cellular gene therapy likely to gain an FDA-approved indication for cancer. These include (1) confirmatory clinical trials since the CD19-targeted CARs are on accelerated track for FDA approval, (2) a need for a Risk Evaluation and Mitigation Strategy, (3) long-term databases and repositories to evaluate CAR T cell and vector/gene insertional toxicities, and (4) reimbursement by Medicare and private payers. Many of these challenges will require new mechanisms that must be developed quickly and could serve as a blueprint for the development of future cellular immunotherapies and gene therapies, which are rapidly advancing for diseases such as multiple myeloma and acute myeloid leukemia. This will be critically important if adoptive T cell therapies can be successfully developed against solid tumor malignancies due to the vast number of potentially eligible patients and the difficulty required for monitoring a large number of products and patients.

For investigators that have been working up to 20 years to translate CAR T cells from the lab to patients, 2017 represents a landmark achievement for their, and countless others’, efforts. However, the long term viability of CAR T cells as a cancer therapy will be ensured or relegated based on the next few years after approval, highlighting the importance of developing insightful and meaningful post-approval clinical trials and regulations. Clinical trials must be designed to confirm survival advantages while also detailing production failure rates, as well as morbidity and mortality rates. Furthermore, independent foundation and/or government regulation concerning the production, administration, and management of CAR T cell therapies and patients will be critical for ensuring similar guidelines are followed by clinical providers, thereby increasing the safety and utilization of these exciting cell therapies. The standards that are established will serve as guidelines for future innovative gene-modified cell therapies.

Declaration of interest

F Locke is on the advisory board of Kite Pharma and is a consultant for Cellular Biomedicine Group Inc. (CBMG). M Davila is on the advisory board of Celyad, Precision Bioscience and Servier. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This manuscript has not been funded.