10 Years of CAR-T: What Does the Future Hold for CAR-T?
As our month of celebrating ’10 years of CAR-T’ nears its end, we explore what to expect from CAR-T in the coming years.
The last decade has hosted a substantial period of progress and development in the advanced therapies arena. As patients who have received CAR-T for hematological malignancies start reaching the milestone of a decade in remission, it leaves no question that CAR-T is leading the way in representing the life-saving potential of these therapies.
With a constant stream of CAR-T news, from positive preclinical data to regulatory fast-track designations and approvals, presented by researchers and biotech companies, it is clear that CAR-T is making waves in mainstream cancer medicine.
However, CAR-T is still in its infancy as a treatment. There are many questions about its future, including: when will we see success with solid tumors and non-cancerous indications, can it demonstrate sustained results and stability across all types of blood cancers, and how will issues surrounding safety and patient access be addressed to allow more patients to reap its life-saving potential?
It’s the Blood Cancer and CAR-T Show
Looking at CAR-T therapies at preclinical through to pre-registration stages, data from GlobalData  demonstrates that the overwhelming majority, 1186 out of 1196, investigational trials are taking place in oncological indications.
Collectively over 90% of the CAR-T drugs in oncological development are for hematological malignancies. This is no surprise considering all successful CAR-T approvals so far are for the treatment of blood cancers – lymphomas, leukemias, and myelomas. See figure 1.
Figure 1. CAR-T Products and the Indications They Are Approved for
Although movement into non-oncological indications is slowly gaining ground, hematological malignancies still unquestionably dominate the CAR-T space. We are likely to see the approval of more CAR-Ts for blood cancers approved in the coming years.
According to Global Data , there are currently six CAR-T drugs targeting hematological malignancies in the pre-registration stages having completed the necessary clinical trials and awaiting registration or approval, 10 CAR-T trials in Phase III and 194 in Phase II, see Figure 2. There we can expect that the next CAR-Ts to gain regulatory approval will help cement CAR-T’s prominence as an effective blood cancer treatment.
A full dive into CAR-T, all its success, and its future potential as a cure for blood cancer, can be found in this recent report >>
Make Room for Solid Tumors
When we break down the data considering all CAR-Ts in preclinical and clinical development into specific indications, solid tumors are seeing the highest number of CAR-T drugs in oncological development. See figure 3
CAR-Ts are yet to replicate the successful therapeutic effects demonstrated in blood cancers in solid tumors. Will this evident exploratory focus on solid tumors change that?
Firstly, we want to look at why there is a hold-up in creating a successfully approved CAR-T targeting solid tumors?
There are currently 143 CAR-T drugs at pre-registration stages up to Phase II investigation for solid tumors, the majority of which – 112 – are still in the early preclinical stages.
The quantity of early phase CAR-T cell studies in solid tumors reflects the diversity of this indication area with multiple antigen targets, but it also reveals the lack of supporting evidence behind any one type of CAR-T for destroying solid tumors.
The biology of solid tumors including, brain, breast, bowel, and kidney cancer, presents CAR-T with many obstacles it doesn’t face when targeting blood cancers.
The solid tumor microenvironment is hostile, hypoxic, and anti-inflammatory with the cancerous cells protected from CAR-T invasion by inflammatory cells, connective tissues, and a poor vascular system in the tumor mass.
Solid Tumor CAR-T Development:
- To combat the issue and enable CAR-Ts to infiltrate the immune-suppressing environment surrounding solid tumors, studies are currently observing CAR-T as a combination therapy – with positive responses reported so far .
- The development of ‘armored’ CAR-Ts, which have been engineered to secrete specific cytokines, have been shown to increase T cell survival, proliferation, and anti-tumor activity, replacing the microenvironment .
- The other main issue with solid tumors is their lack of universal and specifically expressed antigens. Solid tumors vary wildly from one another in different areas and different individuals. This lack of specificity causes difficulty in creating a CAR-T that can identify and also solely interact with the tumor cells. While CAR-T research has yet to result in a breakthrough in solid tumors, preliminary results of tandem CARs – CARs containing two antigen receptors – in preclinical models of breast cancer and glioblastoma  – presented reduced antigen escape and increased on-target anti-tumor activity.
- Another modification to the traditional CAR-Ts for better solid tumor targeting under investigation is the addition of tumor–restricted post-translational modifications targets, for example, over-expressed shortened O-glycan’s, Tn .
- Investigating methods of delivery that improve CAR-T delivery and infiltration of solid tumors has also proved effective in increasing therapeutic activity. Positive preclinical studies of local administration through intraventricular injection of CAR-Ts targeting HER2 and IL13Ra2 in breast cancer and glioblastoma have led to multiple ongoing clinical trials including in brain metastases .
According to data from GlobalData , there are 11 CAR-T drugs presently in Phase II clinical trials for a range of solid tumors.
It is extremely positive to see trials in solid tumors starting to enter the Phase II stage. Some products to note include: Gilead’s Yescarta and brexucabtagene auto excel for generalized solid tumors, SOTIO Biotech AS’s B0XR-1030 for lung cancer, and Bellicum Pharmaceuticals’ BPX-603 for ovarian, gastric, and endometrial cancer, amongst others.
Introducing CAR-T for Non-Cancerous Indications
CAR-T development is also beginning to extend outside of oncology into other therapy areas. These currently include 14 investigational drugs for immunological disorders, 8 for infectious diseases, and 4 for metabolic disorders .
Primarily CAR-T products for indications outside oncology are in the early stages of development. For example, there are 3 CAR-Ts under preclinical research for HIV, plus 1 which has entered into a Phase I trial. Another infectious disease to gain the attention of CAR-T researchers is Covid-19. One CAR-T product, PVX-010, is currently in its preclinical stages. Will we see CAR-T become a player in the treatment and prevention of the spread of infectious diseases?
CAR-T for non-oncological indications in the latter stages of clinical development is presently rare. The trials currently furthest along are in: the infectious disease Epstein-Barr Virus, immunological disorder myasthenia gravis, the hematological disorder idiopathic thrombocytopenic purpura, and the metabolic disorder amyloidosis. Will these trials demonstrate positive results and write a whole new page in the CAR-T story?
Solving the Patient Access Problem
Two areas that pose significant challenges to the commercial success of CAR-Ts are the lack of patient access and safety concerns.
Unfortunately, CAR-T access is a postcode lottery. When receiving treatment patients must attend a specialist treatment center. Fewer than 100 centers in the U.S. are currently certified to administer Yescarta , and in the UK only 8 centers for adults and 9 for children  provide CAR-T treatment.
Because of the complexity of the end-to-end process of CAR-T administration, centers must have the appropriate infrastructure and workforce expertise before they can be approved as CAR-T administration centers.
The nature of CAR-T as an on-time treatment means that there are many logistical intricacies. The time between the collection of patient T cells to the infusion of the genetically engineered cells back into the patient in the U.S. is generally about 17 days for Yescarta and 22 days for Kymriah .
The main resolver to overcome all these patient access issues is funding and investment. This could help provide:
- More medical centers with workforce training and specialized personnel to increase the number of CAR-T administration sites.
- The building of more manufacturing sites closer to sites of patient T cell extraction and infusion, more funds put into specialized equipment to reduce the long manufacturing times, to reduce the waiting times, and the risk of disease progression.
- Greater research into allogenic CAR-T, which would see CAR-T become an off-the-shelf treatment.
When will we see CAR-T become a mainstream and easily accessible cancer treatment?
There are a lot of questions as we enter into the next five to ten years of CAR-T development. It is easy to get excited about the potential of CAR-T after the successes we’ve seen so far and with so many promising products in the pipeline, however there is still a long way to go before we see greater use of CAR-T as a mainstream medicine. One thing is for sure – we will be hearing about CAR-T a lot more.
 Sterner, R. and Sterner, R., 2021. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer Journal, 11(4).
 National Cancer Institute. 2022. CAR T Cells: Engineering Immune Cells to Treat Cancer. [online] Available at: <https://www.cancer.gov/about-cancer/treatment/research/car-t-cells> [Accessed 20 May 2022].
 PHG Foundation. 2022. CAR-T cell therapies. [online] Available at: <https://www.phgfoundation.org/briefing/car-t-cell-therapies> [Accessed 20 May 2022].
 Cancerresearchuk.org. 2022. CAR T-cell therapy | Cancer Research UK. [online] Available at: <https://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/immunotherapy/types/CAR-T-cell-therapy> [Accessed 20 May 2022].
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