In 1989, the Proceedings of the National Academy of Sciences (PNAS) reported the first generation of CAR-T therapy. Although it was quickly put into clinical trials, the efficacy was not satisfactory. In 1998, CD137 (or CD28, ICOS, OX-40), a costimulatory signaling molecule necessary for T cell activation and survival, was assembled into CAR to enhance the expansion and viability of CAR-T cells in vivo. Hence, the second CAR-T technology came into being.

After the first success in mice, the second-generation CAR-T was developed rapidly, with a remission rate of more than 90% in patients with relapsed or refractory acute B-lymphocytic leukemia (ALL). In the past decade, CAR-T cell therapy has rapidly been adopted for clinical use from academic research center.

Here in this article, we will review the challenges and limitations of CAR-T in the past decade and explore the opportunities and possibilities facing CAR-T entering the next decade.

The debut of CAR-T therapy

In addition to successful trials in malignant lymphoma, Kalos et al. published an early report on the treatment of chronic lymphocytic leukemia with CAR-T cells in the 2011 Science Translational Medicine, all of which showed that CAR-T cells targeted at CD19 can induce long-lasting anti-tumor responses and establish memory T cells belonging to CAR-T.

The subsequent success in childhood and adult acute lymphoblastic leukemia (ALL) has turned the world's attention to this emerging therapy. The clinical trial of CAR-T therapy has experienced explosive growth. In the second phase of clinical trials, CAR-T achieved a remission rate of 81% within 3 months, making the US Food and Drug Administration (FDA) first grant CAR-T cell therapy for the treatment of patients with relapsed or refractory B cell leukemia under 25 years of age in 2017. Shortly after that, the FDA immediately approved a second indication for the treatment of adult patients with refractory large B-cell lymphoma.

How to ensure the long-lasting efficacy

How to achieve persistent efficacy is still a challenge for CAR-T therapy. Numerous studies have shown that the persistence of CAR-T cells is closely related to clinical response. The structure and design of CAR-T affects the persistence of CAR-T. The current second-generation CAR, combined with a CD3-ζ signal domain and co-stimulatory domain, is the most common structure in clinical use. This generation of CAR-T cells expands rapidly, and the speed of eliminating tumor cells is also fast. At the same time, CAR-T using the 4-1BB co-stimulation domain can have a longer-lasting effect than CD28 CAR-T cells.

The persistence of CAR-T cells in patients means continuous and effective clinical efficacy. How to avoid the failure of T cells in patients and improve the efficacy is a difficult problem we need to overcome. But fortunately, owing to the leaps and bounds in medical technology advance, relevant reports have shown that it can reverse T cell failure in 2019. But this does not mean that a short-lasting CAR-T is not a good CAR-T. For different diseases, we need different types of CAR-T. For example, long-lasting efficacy is not needed in the treatment of acute leukemia.

Cytotoxicity of CAR-T

The accumulating experience promotes standardized clinical guidelines and increases the safety of CAR-T. Cytokine release and immunocytotoxicity-related neurocytotoxicity are currently the most important and most serious side effects of CAR-T. In the past, when we took CAR-T treatment, we often delayed the persistence because of the unclear understanding of side effects. Now that we have a good understanding of this toxicity, we have established a clinical management approach to these two toxicities, allowing patients to receive treatment safer.

CAR-T therapy and recurrence rate

Although the clinical response rate for the first CAR-T treatment was as high as 90%, the long-term follow-up data was less optimistic, with a 3-month overall response rate of 81%, whereas the 12-month event-free survival rate was only 50%.

We all know that CAR-T cells need to install CAR, which is what we call GPS, according to the specific target of tumor cells. GPS-loaded CAR-T can quickly find tumors. However, in relapsed patients, tumor cells often changes their specific targets so that to CAR-T fails to recognize them. Therefore, in the future, we need to perform more accurate immunoassays on tumors and identify predictive biomarkers that increase the risk of immune escape.

In which field is the future of CAR-T optimistic?

Malignant hematoma
For patients with CD19-positive B-cell leukemia, CAR-T cells can be very effective. However, for patients with negative CD19, there is a risk of recurrence of the disease, and we need to find antigens other than CD19. Patients treated with CD22-targeted CAR-T cells also showed a 73% clinical response rate, comparable to CD19CAR-T. At the same time, CAR-T cells targeting CD19/CD22 or CD19/CD20 dual targeting are also showing promising prospects.

Solid tumor
If CAR-T cells are to further expand their efficacy, conquering solid tumors might be a good way. However, in treating solid tumors, CAR-T cells need to overcome the following problems: how to make limited CAR-T cells around the tumor cells; how to reverse the failure of T cells; how to find specific targets for solid tumors, and so on. At present, a number of CAR-T cells have been studied in solid tumors, and CAR-T cells which are self-expressing immunological checkpoints are also expected to become the hope of CAR-T cells to enter solid tumors.

Cost might be the biggest constraint

Although scientists have been working hard on how to improve the efficacy of CAR-T and expand indications, but for reality, how to reduce the cost of treatment and make it affordable for more patients is an urgent matter.

The two CAR-Ts currently on the market are priced at around $400,000 ($373,000, $475,000) and are still an elusive treatment for most patients. Improving the production process and reducing production costs are expected to lead to a final price decline.

Reference:
1. Liora Schultz, Crystal Mackall. Driving CAR T cell translation forward, Science Translational Medicine (2019)

Author's Bio: 

Creative Peptides has been endeavored to the great cause of conquering various diseases, cancers in particular, by offering various research peptides like checkpoint inhibitors, isotope labeled peptides, antimicrobial peptides, FRET substrates, fibronectin fragments as well as a comprehensive kit of peptide related services like Amino Acids Modification, cyclic peptides, Peptide PEGylation, Surface Plasmon Resonance Imaging, Post-translational Modification, Cyclic Peptide synthesis, Peptide Design, Recombinant Peptide Synthesis.