Last updated: 27 January 2023
See update(s) at the end of the post.
This post is an attempt to provide basic information on CAR-T cell therapy. The information is by no means exhaustive and can be used a starting point for further reading on the subject.
What is CAR T-cell therapy?
Chimeric Antigen Receptor (CAR) T-cell therapy or CAR T-cell therapy is a type of immunotherapy (also known as adoptive cellular immunotherapy) which modifies the immune system of a person with cancer so that it becomes more effective at finding and destroying cancer cells.
What is a Chimeric Antigen Receptor1?
Chimeric antigen receptors (CARs)—also known as chimeric immunoreceptors, chimeric T-cell receptors or artificial T-cell receptors—are receptor proteins that have been genetically engineered to give T-cells the new ability to target a specific antigen on a cancer cell. The receptors are chimeric in that they combine both antigen-binding and T-cell activating functions into a single receptor.
How does CAR T-cell therapy work2?
Of the several types of Lymphocytes, T-cells are a type of white blood cell normally responsible for killing cancerous cells which is why they are used in CAR T-cell therapy. Cancer cells are known to hide from the normal immune system, but through CAR T-cell therapy, T-cells can be made better equipped to find and kill some cancer cells.
- CAR T-cell therapy makes T-cells focus their attention on a substance (that the body thinks is harmful) called an antigen, which is found on the surface of specific cancer cells.
- In the manufacturing of CAR T-cells, a protein is added to the T-cell’s surface via genetic engineering in order to help them achieve this focus. This protein is called a chimeric antigen receptor or CAR.
- This CAR protein is actually made up of 3 proteins: 1 protein that recognizes antigens on the cancer cell and 2 proteins that signal the T-cell to activate when that first protein attaches to an antigen on the cancer cell.
- When a T-cell has a CAR added to it, it is called a “CAR T-cell.”
- CAR T-cells work by floating around the body and looking for cells (e.g. certain cancer cells) that carry the antigen programmed into the CAR protein
- When a CAR T-cell comes in contact with an antigen on a cancer cell, it activates. Activated CAR T-cells multiply and signal to other parts of the immune system to come to the site of the cancer cell. These signalling 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.
To better understand the above, watch this clip and/or this one.
Which cancers is CAR T-cell therapy used to treat?
Examples of cancers that can be treated with CAR T-cell therapies in the EU include:
- diffuse large B-cell lymphoma (DLBCL)
- primary mediastinal large B-cell lymphoma (PMBCL)
- follicular lymphoma grade 3B (FL3B)
For more information on the specific circumstances in which each of the above cancers can be treated with CAR T-cell therapy, please refer to the ‘Product information’ or ‘Package insert’ for each product, accessible via the links provided in the tables below in the section The regulation of CAR-T Cell therapies below.
What is the process for delivering CAR T-cell therapy3?
In general, the steps are as described below but there will likely be some differences in how patients are treated across the globe:
- Collecting the T-cells: T-cells are collected through apheresis. This simple, non-invasive process removes the T-cells from the blood (similar to the method for blood donation) and returns the remaining blood back into the body.
- Supercharging the T-cells: An antibody-like protein called a chimeric antigen receptor (CAR) is inserted on the surface of the T-cells via genetic engineering.
- Multiplying the CAR T-cells: CAR-T cells multiply in the lab until they number in the millions. The cells are then frozen and returned to the patient’s hospital.
- Pre-treatment lymphodepletion: Most patients undergo a brief course of chemotherapy.
- Infusing the CAR T-cells: When the CAR T cells are returned to the patient’s bloodstream, they continue to multiply. They now act as “attacker” cells: seeking out, recognising and destroying cancer cells that have the targeted antigen on their surface.
- After CAR T-cell therapy: Patients stay in the hospital for a minimum of two weeks for monitoring and treatment of side effects, including potential adverse events. CAR T cells can remain active in the body and continue to safeguard the patient against recurrence of the cancer, bringing long-term remission.
3uchicagomedicine.org (note that not all of the text in this section is from this source.)
Some Important points concerning CAR T-cell therapies
In the EU, the following apply:
- Treatment:
- must be administered in a qualified treatment centre
- is intended for autologus use only
- consists of a single dose for infusion
- Patients normally receive pre-treatment (lymphodepleting chemotherapy) unless there are contraindications
- In order to minimise the risk of infusion reactions, the patient is normally pre-medicated with paracetamol and diphenhydramine or another H1-antihistamine, prior to infusion of the CAR-T cell therapy
- Cytokine Release Syndrome (CRS) – can occur after infusion with a CAR T-cell therapy. In the EU, The availability of at least one dose of tocilizumab for use in the event of CRS should be ensured prior to infusion.
The regulation of CAR T-cell therapies
i) In the European Union (EU)
In the EU, CAR T-cell therapy is regulated under Regulation (EC) No 1394/2007 on advanced therapy medicinal products (ATMPs). The ATMP products registered thus far are all gene therapy medicinal products (see table in this blog post on ATMPs)
Kymriah and Yescarta were the first medicines supported through EMA’s PRIority MEdicines (PRIME) scheme to receive positive opinions from the CHMP. The voluntary scheme provides early and enhanced scientific and regulatory support to medicines that have the potential to address to a significant extent, the unmet medical needs of patients . Kymriah was granted eligibility to PRIME on 23 June 2016, for the treatment of acute lymphoblastic leukaemia (ALL). Yescarta was granted eligibility to PRIME on 26 May 2016 for the treatment of diffuse large B-cell lymphoma (DLBCL).
ii) In the US
CAR T-cell therapy is regulated as a gene therapy (GT) product under FDA’s existing framework for biological products. In March 2022, FDA published draft guidance for industry entitled Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products.
This guidance:
- is intended to assist sponsors, including industry and academic sponsors, developing CAR-T cell products. In this guidance, the FDA provides CAR T cell-specific recommendations regarding chemistry, manufacturing, and control (CMC), pharmacology and toxicology, and clinical study design. Recommendations specific to autologous or allogeneic CAR T-cell products are noted in this guidance.
- also provides recommendations for analytical comparability studies for CAR T-cell products.
While this guidance specifically focuses on CAR-T cell products, much of the information and recommendations provided will also be applicable to other genetically modified lymphocyte products, such as CAR Natural Killer (NK) cells or T cell receptor (TCR)-modified T-cells. These related product types can be highly specialized, and in many cases, considerations beyond those recommended in this guidance would depend on the specific product and manufacturing process.
CAR T-cell Products authorised in the EU
Key for acronyms used in the table below:
diffuse large B-cell lymphoma (DLBCL)
primary mediastinal large B-cell lymphoma (PMBCL)
follicular lymphoma grade 3B (FL3B)
high-grade B-cell lymphoma (HGBL)
follicular lymphoma (FL)
B-cell acute lymphoblastic leukaemia (ALL)
The table below details the CAR T-cell products authorised in the EU.
| Company | Product | Active substance | Date of grant of initial EU authorisation | Currently approved indication(s) | Accelerated assessment | Conditional Marketing Authorisation | Orphan designation | Developed via the PRIME scheme |
|---|---|---|---|---|---|---|---|---|
| Janssen-Cilag International NV | Carvykti | ciltacabtagene autoleucel | 25 May 2022 | Multiple myeloma, relapsed or refractory in adults Product Information | Yes | Yes | Yes | |
| Bristol-Myers Squibb Pharma EEIG | Breyanzi | lisocabtagene maraleucel | 4 Apr 2022 | Relapsed or refractory DLBCL, PMBCL, FL3B in adults Product Information | Yes | Yes | ||
| Bristol-Myers Squibb Pharma EEIG | Abecma | idecabtagene vicleucel | 18 Aug 2021 | Relapsed or refractory multiple myeloma in adults Product Information | Yes | Yes | Yes | |
| Kite Pharma EU B.V. | Tecartus | Brexucabtagene autoleucel | 14 Dec 2020 | Refractory ALL (adults aged 26 yrs or over) or Mantle cell lymphoma Product Information | Yes | Yes | Yes | |
| Kite Pharma EU B.V. | Yescarta | axicabtagene ciloleucel | 23 Aug 2018 | Relapsed or refractory HGBL, DLBCL, PMBCL, FL in adults Product Information | Yes | Yes | Yes | |
| Novartis Europharm Limited | Kymriah | tisagenlecleucel | 22 Aug 2018 | Relapsed or refractory ALL (in children and adults up to 25 yrs) or DLBCL (adults) Product Information | Yes | Yes | Yes |
CAR T-cell Products authorised in the USA
Key for acronyms used in the table below:
Mantle cell lymphoma (MLL)
B-cell precursor acute lymphoblastic leukemia (ALL)
The table below details the CAR T-cell products authorised in the US:
| Manufacturer | Product | Active substance | Date of initial US approval | Currently approved Indication(s) | Orphan drug designation | Regenerative Medicine Advanced Therapy(RMAT) designation | Breakthrough therapy designation | Priority Review |
|---|---|---|---|---|---|---|---|---|
| Kite Pharma Inc. | Tecartus | brexucabtagene autoleucel | 1 Oct 2021 | Adults with relapsed or refractory MCL Package insert | Yes | Yes | Yes | |
| Celgene Corporation, a Bristol-Myers Squibb Company | Abecma | idecabtagene vicleucel | 27 Mar 2021 | Adults with relapsed or refractory multiple myeloma Package insert | Yes | Yes | ||
| Kite Pharma, Inc. | Yescarta | axicabtagene ciloleucel | 5 Mar 2021 | Adult patients with b-cell lymphoma refractory or relapsed after first line chemotherapy or Adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy Package insert | Yes | Yes | ||
| Juno Therapeutics Inc., a Bristol-Myers Squibb Company | Breyanzi | lisocabtagene maraleucel | 5 Feb 2021 | Package insert | Yes | Yes | Yes | |
| Novartis Pharmaceuticals Corp. | Kymriah | tisagenlecleucel | 30 Aug 2017 | Package insert | | | | |
The table below details the CAR T-cell products authorised in Great Britain (GB):
| Company | Product | Active substance | Date of initial GB authorisation | Currently approved indication(s) | Conditional Marketing Authorisation | Orphan designation |
|---|---|---|---|---|---|---|
| Bristol-Myers Squibb Pharma EEIG | Abecma | idecabtagene vicleucel | 24 Jun 2022 | Relapsed or refractory multiple myeloma in adults SmPC and PIL | Yes | Yes |
| Gilead Sciences Ltd | Tecartus | Brexucabtagene autoleucel | 30 Nov 2022 | Refractory ALL (adults aged 26 yrs or over) or Mantle cell lymphoma SmPC and PIL | ? | Yes |
| Gilead Sciences Ltd. | Yescarta | axicabtagene ciloleucel | 01 Jan 2021 | Relapsed or refractory HGBL, DLBCL, PMBCL, FL in adults SmPC and PIL | – | Yes |
| Novartis Pharmaceuticals UK Limited | Kymriah | tisagenlecleucel | 01 Jan 2021 | Relapsed or refractory ALL (in children and adults up to 25 yrs) or DLBCL (adults) SmPC and PIL | – | Yes |
If you have any comments concerning this post, please share them via the feedback form.
Updates
| Date | Update(s) |
|---|---|
| 27 Jan 2023 | Table added for CAR-T cell products authorised in GB |