By David Pérez, PhD
In March 2022, the U.S. Food and Drug Administration (FDA) issued its first draft guidance for industry specifically focused on chimeric antigen receptor (CAR) T-cell therapies.1 CAR T-cell products are T cells that have been genetically modified to express T-cell receptors that can recognize and bind to specific antigens on the surface of target cells (such as cancer cells). When the T-cell receptors engage antigens, they activate the T cells that bear them against the target cells that bear the antigens. In recent years, products of this type have shown unprecedented clinical efficiency, and they have become important tools in the fight against diseases.
Under the FDA framework for biological products, CAR T-cell products have been regulated as gene therapy products. Indeed, CAR T-cell products will continue to be covered by a January 2020 FDA guidance concerning Investigational New Drug (IND) applications for human gene therapy products.2 And now CAR T-cell products will also be covered by the newly issued FDA guidance, which provides CAR T cell–specific recommendations regarding chemistry, manufacturing, and control (CMC); pharmacology and toxicology; and clinical study design. This guidance applies not only to CAR T-cell products, but also to other genetically modified lymphocyte products such as CAR natural killer (NK) cells or T cell receptor–modified T cells.
What does the FDA expect in your IND application?
CAR T cells are complex products that can contain multiple functional elements as part of the chimeric construct. The nature of these functional elements, how they are introduced into the cells through a vector, the cellular starting material, and the final drug product formulation are all critical to product safety, specificity, and efficacy.
CAR construct
CAR constructs typically contain two types of domains: antigen recognition domains and signaling domains. The FDA recommends providing an assessment of the ability of each antigen recognition domain to specifically bind to its target molecules. Whenever immunogenicity is reduced (for example, through humanization by complementarity-determining region grafting), the impact on target binding and biological activity should be evaluated.
The FDA also recommends that the functionality of signaling domains be thoroughly demonstrated, and that information be provided describing how CAR components (that is, transmembrane domain, hinge region, and linker regions) affect CAR T-cell specificity and activity.
Vector
The vector should be well characterized prior to initiation of clinical studies, and full cGMP requirements should be met during Biologics License Application review as well as during the validation of all analytical assays. The information that the FDA expects about the vector includes vector structure (including justification on additional functional elements other than the CAR construct), manufacturing, release testing (including potency test, vector concentration, and vector safety), and stability.
Information on the characterization and testing of Master Cell Banks and Working Cell Banks should also be provided. Vectors that integrate into the genome can provide long-term transgene expression compared to nonintegrating vectors, but the FDA will expect long-term follow-up due to the increased risk of delayed adverse events.
Cellular starting material
The cellular starting material is critical for CAR T-cell quality and function, and it is generally obtained by leukapheresis of patients (for autologous products) or healthy donors (for allogeneic products). Safety and regulatory considerations differ for autologous and allogeneic products.
In this guidance, the FDA considers risks due to previously administered CAR T-cell products in the cellular starting material. It recommends an evaluation of levels of residual CAR T cells and vector copy number for the newly introduced and previously administered CAR T cells in the starting material and final product.
Autologous cellular starting material represents a major source of lot-to-lot variability. Accordingly, all procedures used for handling leukapheresis starting material from collection to the start of the manufacturing process should be described. Moreover, this recommendation should be followed at all leukapheresis collection sites, and it should cover related activities such as shipping and handling, as well as the validation of the shipping process and any hold or cryopreservation steps.
The FDA also recommends establishing acceptance criteria for leukapheresis to increase the probability of manufacturing success. These criteria may include minimum cell number, viability, percentage of CD3-positive cells, etc.
CAR T-cell product
To minimize variability due to the CAR-T cell manufacturing process, the FDA recommends having a well-controlled process, one that uses qualified and safe ancillary materials, in-process controls, in-process testing, and testing of intermediate and final products. The safety of the final product is also ensured by using validated aseptic processing under cGMP conditions. This approach is necessary because CAR T cells cannot be terminally sterilized.
The ability of the proposed manufacturing process to produce CAR T cells is demonstrated through the production of developmental or engineering batches using starting material from healthy donors or from patients.
CAR T cells can be formulated for fresh infusion or cryopreserved for later administration. The choice of formulation depends on the product development strategy and practical constraints. The guidance discusses the advantages and disadvantages of both approaches regarding the limited time to perform release testing and risk of toxicity due to the cryoprotectant.
Analytical testing of CAR T cells is also necessary to ensure product safety, identity, quality, purity, and strength (including potency) of the investigational product. These analytical methods are often complex and require extensive development. The FDA recommends starting early with the development of such analytical methods. In addition, the FDA provides recommendations on the quality attributes that should be tested. It notes that cell viability, identity, purity, and strength may be assessed by flow cytometry. Other analytical tests may determine vector copy number and potency.
Management of manufacturing changes (comparability)
The development of CAR T-cell products often requires changes to the manufacturing process. Prior to implementation of any change, a risk assessment to evaluate the potential impact of the intended change on product quality and safety should be conducted using developmental lots.
Substantial changes to the vector or CAR-T cell manufacturing processes, including new manufacturing sites, should be supported by comparability studies. This requires side-by-side analysis pre- and post-change using the same cellular starting material, following the principles of ICH Q5E. The complexity of comparability assessments will depend on the extent of change.
For example, if there are changes in the CAR construct or changes from autologous to allogenic cellular starting material, the new process will be understood to generate a new product. If there is insufficient evidence to demonstrate analytical comparability, additional nonclinical or clinical studies may be requested.
Single- versus multisite manufacturing
For the first time, the FDA discusses the advantages and disadvantages of the use of single- versus multisite manufacturing in a guidance. Single centralized sites have the advantage of reducing potential product variability; however, there may be logistical concerns with cryopreservation or shipping of the different materials. Multisite manufacturing may shorten the timeline from leukapheresis collection to administration for autologous products; however, differences between facilities may contribute to product variability.
How has this guidance been received?
Since the release of the new draft guidance, many public comments have been offered by biopharmaceutical industry and clinical personnel.3 Some of these comments pertain to the FDA’s recommendation that “evaluation of the previously administered CAR T-cell levels in the cellular starting material may be appropriate.”
Various stakeholders noted that this recommendation would be very difficult for a manufacturer to follow if another manufacturer had been the one to provide the earlier CAR T-cell therapy. There could be complications over proprietary technologies.
Topics explored in other comments include change management and the possibility that the guidance could be applied to products other than CAR T cells. Stakeholders observed that the guidance focused on major changes but didn’t resolve uncertainties over the management of minor changes. Also, stakeholders suggested that the FDA could extend the guidance to cover other genetically modified lymphocytes.
Conclusions
The new FDA guidance is a significant effort by the FDA to provide clear and specific recommendations for the development of CAR T-cell products regarding vector and CAR T-cell manufacturing and testing, cellular starting materials, change management and the design of comparability studies, and single-site or multisite manufacturing.
Since the guidance is still a draft, several comments have been raised regarding starting materials, change management, and the manufacture of genetically modified lymphocytes other than CAR T cells. It is now up to the FDA to determine how the comments may influence the implementation of the guidance.
David Pérez, PhD ([emailprotected]), is principal consultant, regulatory and access, for Parexel.
References
1. U.S. Food and Drug Administration. Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products: Draft Guidance for Industry. Posted March 2022. Accessed August 2022.
2. U.S. Food and Drug Administration. Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs): Guidance for Industry. Posted January 2020. Accessed August 2022.
3. https://www.regulations.gov/document/FDA-2021-D-0404-0001/comment.
FAQs
Key Points from the FDA's Guidance for CAR T-Cell Products? ›
To minimize variability due to the CAR-T cell manufacturing process, the FDA recommends having a well-controlled process, one that uses qualified and safe ancillary materials, in-process controls, in-process testing, and testing of intermediate and final products.
What are the three biggest challenges with manufacturing CAR T cells? ›- Supply Constraints. All cell therapy products, whether autologous or allogeneic, are dependent upon the cells and tissues from which they are manufactured. ...
- Scalability Issues. ...
- Storage and Logistics Challenges.
It has been recommended that “Long Term Follow-Up” be performed for as long as 15 years based on risk with 5 years of annual physical and serological examinations and 10 years of annual queries of recipient of investigational products.
How many companies currently have FDA approved CAR T-cell therapies? ›The 5 FDA approved CAR T-cell therapies
Kymriah™ (tisagenlecleucel) Yescarta™ (axicabtagene ciloleucel) Tecartus™ (brexucabtagene autoleucel)
CAR-T therapy enhances the effectiveness of T cells. protocol for CAR-T therapy: Blood is taken from the patient and T cells are isolated and removed in a process called apheresis or leukapheresis. The remaining blood is transfused back to the patient.
When did the FDA approve CAR T-cell therapy? ›On February 28, the Food and Drug Administration (FDA) approved ciltacabtagene autoleucel (Carvykti) for adults with multiple myeloma that is not responding to treatment (refractory) or has returned after treatment (relapsed).
What are the challenges of CAR T-cell production? ›Despite their success, there are major limitations to CAR T-cell therapy that still must be addressed, including life-threatening CAR T-cell associated toxicities (cytokine release syndrome, neurologic toxicities, prolonged cytopenias, etc.), inhibition and resistance in B-cell malignancies, antigen escape, limited ...
What are the shortcomings of CAR T-cell? ›One of the main problems of CAR-T therapy is the identification of an ideal antigen, because most antigens in tumor cells are also present in normal cells of the human body. As a result, in the process of attacking tumor cells, activated T cells can also inflict damage on normal tissues.
What are the drawbacks of CAR T-cell therapy? ›A major hurdle to CAR-T cell therapy is severe toxicities. The most common toxicities following infusion of CAR-T cells are CRS, neurologic toxicity, tumor lysis syndrome (TLS), on-target-off-tumor effects, anaphylaxis, and hematologic toxicities (19, 86, 87) ( Figure 4 ).
What is the FDA guidance common rule? ›The Common Rule, which was first promulgated in 1991, applies to human subjects research that is conducted, supported or otherwise subject to regulation by a federal department or agency that has, through administrative action, made the policy applicable to such research, including the U.S. Department of Health and ...
What is FDA final guidance? ›
Guidance documents describe FDA's interpretation of our policy on a regulatory issue (21 CFR 10.115(b)). These documents usually discuss more specific products or issues that relate to the design, production, labeling, promotion, manufacturing, and testing of regulated products.
What is the FDA Six Year Rule guidance? ›The six-year provision enables FDA to use certain data in taking the regulatory actions specified in 520(h)(4) of the act. It does not authorize FDA to disclose data that would otherwise be protected from disclosure.
Who is the leader of CAR-T therapy? ›Leaders of the CAR-T Cell Therapy Industry
Zelig Eshhar from The Weizmann Institute of Science, created the world's first “chimeric antigen receptor” (CAR).
| Company | Total patents (2010 - 2021) | Premium intelligence on the world's largest companies |
|---|---|---|
| Amgen | 55 | Unlock company profile |
| Atara Biotherapeutics | 47 | Unlock company profile |
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| BioNTech | 89 | Unlock company profile |
Fifth-generation. The fifth generation CAR-T cells contain an extra intracellular domain than their predecessors. The CARs comprise truncated intracellular domains of cytokine receptors (e.g., IL-2R chain fragment) with a motif for binding transcription factors such as STAT-3/5.
What are the steps in CAR-T therapy? ›- collecting your T-cells.
- converting your T-cells into CAR T-cells at a special laboratory.
- growing hundreds of millions of your CAR T-cells in the laboratory.
- preparing your body for the CAR T-cells, usually with chemotherapy.
- infusing the CAR T-cells into your body.
For adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). For young adult patients up to age 25 with relapsed or refractory acute lymphoblastic leukemia (ALL).
What does CAR-T therapy require? ›CAR T-cell therapy is a form of immunotherapy that uses specially altered T cells — a part of the immune system — to fight cancer. A sample of a patient's T cells are collected from the blood, then modified to produce special structures called chimeric antigen receptors (CARs) on their surface.
What is the current state of CAR T-cell therapy? ›Chimeric antigen receptor T-cell (CAR-T) therapy has been approved for relapsed/refractory B-cell lymphomas and greatly improves disease outcomes. The impressive success has inspired the application of this approach to other types of tumors.
What was the first FDA approved CAR-T therapy? ›Abstract. The first chimeric antigen receptor T-cell therapy, tisagenlecleucel, received FDA approval for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia who haven't responded to standard therapy or who have relapsed at least twice.
What is the success rate of CAR T-cell therapy? ›
As far as the CAR T-cell success rate goes, there are several studies to prove that this new approach is working: According to data provided by the Medical University of Chicago1, the CAR T-cell therapy success rate is about 30% to 40% for lasting remission, with no additional treatment.
What are the two major toxicities associated with patients who receive CAR T cells? ›Introduction to CAR T-cell toxicities
Acute anaphylaxis and tumor lysis syndrome (TLS) have occurred following infusion of CAR T cells.
How long do CAR T cells persist? CAR T-cell therapy is a “living drug” and intended to remain in the body fighting cancer. For most people, CAR T is a one-time treatment and the T cells remain in the body for months and years.
What is the killing mechanism of CAR T cells? ›Activated CAR T cells multiply and signal to other parts of the immune system to come to the site of the cancer cell. These signaling proteins are called cytokines. All of these cytokines and activated T cells then cause significant inflammation focused at the cancer cell, which causes the cancer cell to die.
Why do CAR T cells fail? ›There are several reasons why CAR T-cell therapy may fail: The cancer cells may stop making the antigen targeted by the therapy, which means the T-cells that were engineered for that specific antigen won't work. This is called antigen loss.
What are problems with T cells? ›T-cell immunodeficiency diseases include severe combined immunodeficiencies (SCIDs), Wiskott-Aldrich syndrome, ataxia telangiectasia, DiGeorge syndrome (22q11. 2 deletion syndrome), immuno-osseous dysplasias, dyskeratosis congenita, and chronic mucocutaneous candidiasis.
What is the difference between CAR T cells and TCR? ›As mentioned previously, CAR T cells have receptors that target naturally occurring antigens. Aside from loaning out T lymphocytes, the immune system plays no role in CAR T-cell therapy. TCR therapy, on the other hand, relies on the MHC to mark cancer cells with recognizable antigens.
What are the neurological complications of CAR T-cell therapy? ›Neurological toxicity associated with CAR T-cell therapy, known as immune effector cell-associated neurotoxicity syndrome (ICANS), affects approximately 50 percent of recipients. Symptoms include confusion, delirium, aphasia, impaired motor skills, and somnolence.
Does CAR T-cell therapy work for all cancers? ›They have a new receptor so they can bind to cancer cells and kill them. Different types of cancer have different antigens. Each kind of CAR T cell therapy is made to fight a specific kind of cancer antigen. So a CAR T cell therapy made for one type of cancer won't work against another type of cancer.
How can CAR T-cell therapy be improved? ›Cell intrinsic blockade of PD-1 signaling is another promising method of combating exhaustion in CAR T cells. The expression of a dominant-negative PD-1 receptor has been shown to improve CAR T functional persistence and protect against exhaustion.
Is FDA guidance mandatory? ›
Guidance is not legally binding on the public or FDA.
What is an FDA proposed rule? ›Proposed Rules
When FDA plans to issue a new regulation or revise an existing one, it places an announcement in the Federal Register on the day the public comment period begins. Published every weekday, the Federal Register is available at many public libraries and colleges, and on the FDA Web site.
Part 11 requires you to have a complete version history available for every quality document in your system, through the: “Use of secure, computer-generated, time-stamped audit trails to independently record the date and time of operator entries and actions that create, modify, or delete electronic records.”
What are the five important stages of drug approval according to FDA? ›- Step 1: Discovery and Development.
- Step 2: Preclinical Research.
- Step 3: Clinical Research.
- Step 4: FDA Drug Review.
- Step 5: FDA Post-Market Drug Safety Monitoring.
Level 1 guidances set forth the agency's initial interpretations of new significant regulatory requirements; describe substantial changes in FDA's earlier interpretation or policy; and deal with complex scientific or highly controversial issues.
What is FDA 510 K summary guidance? ›A 510(k) requires demonstration of substantial equivalence to another legally U.S. marketed device. Substantial equivalence means that the new device is as safe and effective as the predicate. the information submitted to FDA demonstrates that the device is as safe and effective as the legally marketed device.
What is FDA Regulation 21? ›Title 21 of the CFR is reserved for rules of the Food and Drug Administration. Each title (or volume) of the CFR is revised once each calendar year. A revised Title 21 is issued on approximately April 1st of each year and is usually available here several months later.
What is Rule 204 FDA? ›Section 204 of the FDA Food Safety Modernization Act (FSMA) requires the FDA to designate foods for which additional recordkeeping requirements are appropriate and necessary to protect public health.
What is FDA Level 2 guidance? ›(2) “Level 2 guidance documents” are guidance documents that set forth existing practices or minor changes in interpretation or policy. Level 2 guidance documents include all guidance documents that are not classified as Level 1. (3) “You” refers to all affected parties outside of FDA.
Is CAR-T fda approved? ›Cancers with FDA-approved CAR T-cell therapies
The Food and Drug Administration (FDA) has approved six CAR T-cell therapies: Abecma (idecabtagene vicleucel) Breyanzi (lisocabtagene maraleucel) Kymriah (tisagenlecleucel)
What is the most logical approach to improve CAR T-cell therapy? ›
Combinational antigen recognition is the most logical way to improve the safety of cancer therapy.
Who was the first CAR T-cell patient? ›Emily Whitehead, first pediatric patient to receive CAR T-cell therapy, celebrates cure 10 years later. Unwilling to accept this outcome, her family came to CHOP in the hopes that Dr. Stephan Grupp, a pioneer in the field of cellular immunotherapy, could provide the miracle they were looking for. Dr.
Who owns CAR T-cell therapy? ›Novartis pioneered the introduction of CAR-T cell therapy as an approved treatment for B-cell malignancies. Since 2012, Novartis has partnered with the University of Pennsylvania, leading to the first approved CAR-T cell therapy in any disease state.
Who are the major players in CAR T-cell therapy? ›- Novartis AG.
- Bristol-Myers Squibb Company.
- Johnson & Johnson.
- Sorrento Therapeutics, Inc.
- Gilead Sciences, Inc. ( Kite Pharma)
In 2012, Carl June, MD, a pioneer in the development of chimeric antigen receptor (CAR) T-cell therapy, helped treat Emily Whitehead, the first child to receive CAR T-cell therapy on an experimental basis.
Is CAR T-cell therapy a last resort? ›Until last year, CAR T-cell therapy was considered a last resort for patients who had previously undergone chemotherapy and a stem cell transplant. That changed in April 2022 when the FDA approved axicabtagene ciloleucel (Yescarta) for use in patients with large B-cell lymphoma after only 1 treatment failure.
Are CAR T cells CD4 or CD8? ›The surface of CAR T cells can bear either of two types of co-receptors, CD4 and CD8. These two cell types, called CD4+ and CD8+, respectively, have different and interacting cytotoxic effects, and it appears that therapies employing a 1-to-1 ratio of the cell types provide synergistic antitumor effects.
What was the first CAR T-cell product? ›2002 —First effective CAR T cells developed
The MSK team builds the first effective CAR T cells, targeted against a prostate cancer antigen. These second-generation CARs T cells are able to survive, proliferate, and kill prostate cancer cells in the lab, establishing the feasibility of CAR T cell therapy.
Tocilizumab (Actemra®) is approved for the treatment of adults and pediatric patients 2 years of age and older with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome (CRS). You can read more about this drug here.
Which CAR T-cell therapy is approved by FDA for mantle cell lymphoma? ›USFDA has approved brexucabtagene autoleucel (Tecartus, KTE-X19), a novel CAR T-cell therapy to be used in patients with MCL who have not responded to previous treatments or have relapsed. The FDA approved this new treatment depending on the outcomes of the ZUMA-2 clinical trial.
What was the first approved CAR T-cell therapy? ›
2002. The MSK team builds the first effective CAR T cells, targeted against a prostate cancer antigen. These second-generation CARs T cells are able to survive, proliferate, and kill prostate cancer cells in the lab, establishing the feasibility of CAR T cell therapy. An even more promising CAR target lay ahead.
Is CAR T-cell therapy FDA approved for lymphoma? ›CAR T-cell therapies are FDA approved for: Aggressive relapsed or refractory large B-cell lymphoma including diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, and transformed follicular lymphoma. Relapsed or refractory mantle cell lymphoma. Relapsed or refractory follicular lymphoma.
How successful is CAR-T therapy? ›What is the success rate of CAR T-cell therapy? In studies, 9 out of 10 people with acute lymphoblastic leukemia whose cancer didn't respond to other treatments or whose cancer came back had full remission with CAR T-cell therapy. Remission means the cancer can't be detected in tests.
How many people have been treated with CAR-T therapy? ›Since 2017, when CAR (chimeric antigen receptor)-T cells were green-lighted as the first modified therapeutic cells by the Federal Drug Administration (FDA) to treat leukemia, five similar products have since been approved and more than 20,000 people have been treated with this game-changing immunotherapy.
What is one major side effect of CAR T therapy? ›While the therapy can lead to long-lasting remissions for some patients with very advanced cancer, it can also cause neurologic side effects such as speech problems, tremors, delirium, and seizures.
What does CAR T therapy require? ›CAR T-cell therapy is a form of immunotherapy that uses specially altered T cells — a part of the immune system — to fight cancer. A sample of a patient's T cells are collected from the blood, then modified to produce special structures called chimeric antigen receptors (CARs) on their surface.
What are the disadvantages of CAR T-cell therapy? ›A major hurdle to CAR-T cell therapy is severe toxicities. The most common toxicities following infusion of CAR-T cells are CRS, neurologic toxicity, tumor lysis syndrome (TLS), on-target-off-tumor effects, anaphylaxis, and hematologic toxicities (19, 86, 87) ( Figure 4 ).
What type of cancers does CAR T-cell therapy treat? ›The types of cancer that are currently treated using CAR T-cell therapy are diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma, multiple myeloma, and B-cell acute lymphoblastic leukemia (ALL) in pediatric and young adult patients up to age 25.
What is new in CAR T-cell therapy? ›Solid tumor advances. Chimeric antigen receptor (CAR) T cell therapy has been an amazing advance for treating blood cancers like leukemia, lymphoma and multiple myeloma. Now, it is showing promise for solid tumors — from lung cancer to kidney cancer to bone cancer — as well.
What is the new FDA approved treatment for lymphoma? ›FDA has approved Epkinly (epcoritamab-bysp) injection for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B‑cell lymphoma after two or more lines of systemic therapy.
Is CAR T-cell therapy available in the US? ›
Several CAR T cell therapies have been approved by the U.S. Food and Drug Administration (FDA). All approved products use T cells taken from the patient. Some clinical trials use T cells taken from donors.