The Case for Early Regulatory Consideration for Clinical Development of Chimeric Antigen Receptor T cell (CART)

By Jessica Lee, VP, Regulatory Strategy, Head, Cell/Gene Therapy

Chimeric Antigen Receptor T cell (CART) has revolutionized the treatment of hematological malignancies, including B-cell acute lymphoblastic leukemia, B-cell lymphomas, and multiple myeloma. Currently, there are five autologous CART therapies approved for various hematologic malignancies. However, there are limitations in producing autologous CART products, including manufacturing delay or failure. Hence, the next clinical milestone will very likely be the development of allogeneic CART therapies that could offer off-the-shelf products with immediate availability as an on-demand therapeutic option for patients with high unmet medical needs.

Every potential CART product is unique, since it is by definition genetically modified to enable recognition of a desired target antigen for therapeutic purposes. Product development involves new technologies, novel production, and therapy platforms, which produce extra challenges from a regulatory perspective. It follows that companies should communicate with regulatory authorities early in clinical development to discuss regulatory requirements specific for each product before submitting an Investigational New Drug Application (IND). In addition, companies should consider the regulatory landscape when making portfolio decisions and take advantage of the expedited development programs specific for cell and gene therapy to fulfill unmet medical needs.

For multi-national clinical trials, companies should communicate with regulators across different regions to discuss their specific regulatory requirements. While alignment among regulatory agencies in different regions is underway to harmonize the pathways for advanced cellular therapies, universal international standardization is not yet a reality. Uncertainty persists about different regulatory requirements and outlooks on the data packages required for approval of adoptive cellular products that companies need to address.

Managing Inherent Challenges

The development, manufacture, testing, and clinical assessment of CART products is challenging. Careful design and appropriate testing of the CART transgene and delivery vector are critical to product safety, specificity, and function. 

Preclinical evaluation of CART is essential to establish that it is reasonably safe to administer the product in a clinical trial. Due to the inherent biological complexity, variability, and limited availability of suitable animal models to test the safety and activity of each specific CART product, preclinical testing of CART products is not always feasible. To support the use of each CART in a proposed clinical trial, a case-by-case preclinical testing strategy will apply. This strategy might include using in vivo, in vitro, or in silico testing in conjunction with available clinical and preclinical data from related products.

Well-designed Early Phase clinical studies are crucial to understand the safety, preliminary evidence of efficacy, and feasibility of the manufacturing process for individual CART products. 

Meeting Clinical Objectives

A primary objective of Early Phase clinical trials should be a safety assessment. Other objectives might include determination of optimal dosage, pharmacokinetic/pharmacodynamic (PK/PD) studies, evaluation of clinical activity or efficacy, and selecting an appropriate population for further clinical studies to investigate efficacy and safety.

The followings are some of the key clinical considerations for Early Phase development of CART in oncology.

  • Study design

For Early Phase First-in-Human trials without available safety information, treating several subjects simultaneously could represent an unreasonable risk. To protect the safety of study subjects, consider staggered enrollment to limit the number of subjects who might be exposed to an unanticipated risk within a cohort, followed by staggering between cohorts.

  • Study population

Due to considerable toxicities of CART, consider enrolling subjects with severe or advanced disease for whom there is no satisfactory alternative treatment options in Early Phase trials.

Since CART products target specific antigen(s) expressed by the cancer cell, Early Phase trials can include subjects with a common target antigen regardless of cancer type (tissue-agnostic approach). However, potential disparities exist in underlying comorbidities, prior treatment, pre-existing tumor burden on toxicities, and differences in dose response relationship. Therefore, it is advisable to assign subjects to separate cohorts based on disease type, and to evaluate the dose-response relationship and severity of toxicities through parallel dose-escalations between these cohorts in Early Phase trials.

The anti-tumor effect of the CART depends on the binding of the CART with the cognate antigen (biomarker) expressed on the cancer cell; thus, it is reasonable to enroll patients whose tumors express the specific biomarker targeted by the CART. If the intended population will include only those subjects whose tumors test positive for the specific biomarker, consider including a detailed description of the companion diagnostic test in the clinical protocol to facilitate the process of study-risk determination.

  • Treatment plan

The dose selection for CART is complex. Consideration includes dose selection, dose escalation schema, justification of starting dose and of repeat dose if planned, and potential for production-related issues. (These issues might include, for example, feasibility assessment of potential manufacturing delay or failure including poor cell harvest.)

  • Safety evaluation and monitoring

Safety considerations for CART include the risks associated with cell procurement for autologous CART, concomitant therapy (such as high-risk lymphodepletion regimen prior to CART administration), and toxicity associated with CART, A detailed safety-monitoring plan must be in place to protect the safety of study subjects and address potential toxicities associated with CART. This plan should include, but not be limited to, monitoring cytokine release syndrome, neurotoxicity, and potential off-target or on-target/off-tumor toxicity. In addition, the clinical protocol should include well-defined criteria for dose-limiting toxicity (DLT) and stopping rules.

  • Long-term follow-up

Since CART is a living drug capable of proliferation after administration, consider including a long-term follow-up plan in the protocol to determine the duration and persistence of the administered CART. The follow-up duration for subjects after CART administration depends on the underlying disease, persistence of the CART, and the CART vector. In general, subjects should be followed for 15 years after treatment with CART containing an integrated transgene.


Over the next few years, it is very likely that the development of optimized next-generation CARTs will emerge. These CARTs may well display better tumor selectivity, better tumor access capabilities, and increased activity in an immunosuppressive context. On one hand, it is undebatable that adoptive cellular therapy using CARTs shows promise for cancer therapy and has moved rapidly from bench to clinic. On the other hand, many of the CART products now in testing are complex and the first of their type without available safety information. This, combined with inherent treatment-related toxicities associated with CART therapy, makes safety assessment of potential risks associated with CART therapy a priori from a regulatory perspective. Given the field’s fast-moving landscape, it is crucial that companies interact with regulatory agencies early in clinical development and think ahead to ensure that they are part of tomorrow’s landscape.


Please be advised that my comments are an informal communication and represent my own judgement.

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