June 25, 2024

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The next generation of CAR-T cells will overcome current shortcomings?


The next generation of CAR-T cells will overcome current shortcomings?

Researchers from the University of Pennsylvania in the United States described the current obstacles hindering the efficacy of CAR-T cells in the treatment of hematological malignancies in a specific disease manner, and reviewed recent innovations aimed at improving the efficacy and applicability of CAR-T cells.

The overall goal is to establish a framework , Began to incorporate this form of treatment into the standard medical management of blood cancer.

The next generation of CAR-T cells will overcome current shortcomings?



Specific disease disorders of CAR-T cells


Acute Lymphoblastic Leukemia (ALL)

In the past, stem cell transplantation was the last-line treatment for patients with relapsed/refractory B-ALL. Now they can receive CD19-directed CAR-T cell therapy.

CAR-T cell therapy has been successful in this disease, and multiple research groups, including ourselves, report that the complete response (CR) rate is 80%.

Although we have seen success in CD19-directed CAR-T cells in pediatric r/r B-ALL patients in our own trials, with 19BBzCAR, the 12-month relapse-free survival rate after infusion was 59%.

Other trials, using different costimulatory domains, pre-determined CD4:CD8 ratios, and using different B cell target antigens, reported that the recurrence rate after CAR treatment can reach 50% after 12 months of pediatric B-ALL infusion.

It shows that the persistence of remission is still a problem for this indication and has nothing to do with CAR design.

Studies have shown that CAR-T cells can swallow target antigens from the cells and transfer them to themselves, thereby promoting self-cannibalization of CAR-T cells and reducing the overall anti-tumor efficacy.

These observations highlight the key role of antigen expression in regulating CAR function, persistence, and targeting extra-tumor toxicity.

Antigen-positive recurrence in B-ALL. When treated with 1928z CAR, it is often more common, because this CAR design has a shorter durability than 4-1BB and cannot maintain the immune pressure required for antigen escape.


Chronic Lymphocytic Leukemia (CLL)

CLL is a mature B-cell malignant tumor, which accounts for the largest proportion of adult leukemia diagnoses in the United States.

Due to the heterogeneity of the disease progression, immunosuppressive microenvironment and prior treatment for a variety of T cells in the interstitial volume factors such as the treatment of CLL patients remains however non often challenging.

Although there are many standard treatments available, most of them are not curative except for allogeneic stem cell transplantation.

Clinical trials of CD19-targeted CAR T cell therapy have shown that there is a long-lasting anti-tumor response in r/rCLL, but only a small proportion of patients (26%) have this response.

This recovery rate is in sharp contrast with the recovery rate of CTL019 in the treatment of pediatric R/R B-ALL. Additional biological verification of the excellent clinical impact of non-depleted T cells in anti-cancer by treating human leukemia in immunodeficient mice with unmanipulated or CD8+CD27+PD1—depleted CAR-T cells .

The removal of this newly discovered clinically relevant population resulted in severe blockage of the anti-leukemia response, thus confirming its role in mediating the response.

In view of the poor expansion of CAR-T cells in CLL and the infrequent persistence, the confirmation of the mechanically related cell population strongly indicates that the function and frequency of memory cells are the key mediators of the clinical response of CTL019, and provides effective and efficient production for other groups. Roadmap for cell products.


Non-Hodgkin’s Lymphoma (NHL)

NHL is a large type of blood cancer that originates in the lymphatic system.

Among the many diagnoses of NHL, diffuse large B-cell lymphoma (DLBCL) is the most frequently occurring subtype, accounting for 32.5% of all NHLs. In ZUMA-1, 67% of the patients with the lowest tumor burden reached the 1-year remission time point, and only 4% and 7% had grade 3 CRS and neurotoxicity, respectively.

Relatively speaking, 27%, 31%, and 12% of patients in the quartile with higher tumor burden achieved remission at the same time point, respectively. In the CD19-directed NHL CAR-T cell test, the mechanism of resistance and relapse is still under investigation.

However, as of the 2018 ASH meeting report on the ZUMA-1 trial, 7/21 relapses were due to CD19-disorders, and the other 14 were CD19+. Antigen-negative recurrence of lymphoma is rare, but it has also been shown in other studies using CD1928zCAR-T cells to treat lymphoma; however, it is not yet known whether the mechanism of antigen loss is similar to that of B-ALL


Multiple myeloma ( MM )

MM is a plasma cell tumor characterized by the clonal proliferation of malignant plasma cells in the bone marrow.

Although myeloma is mainly found in the bone marrow, malignant cells may escape the bone marrow and form tumors on soft tissues and organs. Patients with extramedullary disease usually have a poor prognosis.

Researchers using biological site BCMA CAR in MM showed that in patients with extramedullary lesions, CAR-T cells took longer to relieve extramedullary lesions than it took to eliminate intramedullary lesions.

In addition, due to the increased time for BCMA patients to relieve extramedullary disease, 6 of 7 relapsed or PD BCMA patients have detectable anti-CAR antibodies in the blood, which is accompanied by a decrease in the level of CAR-T cells in the blood.

Therefore, it is necessary not only to treat malignant clones, but also to treat the microenvironment of BM and extramedullary lesions.



Common barriers of CAR T cells and the cost of common solutions for hematological malignancies


In addition to the drug resistance mechanism of specific diseases, we can broadly define the general obstacles that prevent CAR-T cells from being widely used in the treatment of hematological malignancies (Figure 1).

First of all, the most important thing is the cost of manufacturing genetically modified cell products for patients.

Tisagenlecleucel and Axicabtagene are the first two CAR-T cell products approved by the FDA, with prices of US$475,000 and US$200,000, respectively.

This is a huge expense, which brings significant economic and personal financial burdens to insurance institutions and patients. The cost of this therapy is caused by two factors, namely the production of the drug and its clinical safety management.


The proof-of-concept trial and the second phase trial have confirmed the potential of CAR-T cell therapy to treat blood cancer.

Obstacles related to the manufacturing process and high cost of current therapies prevent all eligible patients from transitioning from a boutique state to standard care treatment.

Due to the high cost of CAR-T cell therapy and the consequent lack of accessibility, optimized manufacturing and CAR design will be the focus of this field.

There are several strategies to reduce costs, the most prominent being monomeric or allogeneic donor “off-the-shelf” CAR (UCAR) T cells.

UCAR-T cells are usually produced by healthy donor (HD) PBMCs, but theoretically they can also be produced by induced pluripotent stem cells (iPSCs) or embryonic stem cells.

Manufacturing a healthy donor-sourced UCAR-T cell can produce multiple bottles of final CAR T-cell product from a single blood draw, thus allowing multiple patients to be treated from a single manufacturing run.

In addition, a bank of UCAR-T cells expressing different HLA subtypes can be created to match patients.

Therefore, the use of UCAR greatly reduces the labor required to produce previously personalized cell products and should reduce the overall price of the drug.

Infusion time

The time between the collection of white blood cells and the infusion of the cell product, commonly referred to as the “venous to vein time”, remains an obstacle for patients with aggressive diseases and continues to lead to patient death.

In the study, 13% of patients died due to disease progression before receiving autologous products. In addition, in a CTL019 trial for B-ALL, 7.6% of enrolled and albumin patients died before infusion.

In addition to bridging therapies that can help control the disease during this period, manufacturing strategies to reduce this vein-to-venous time must also be developed.

In fact, in the preclinical mouse ALL model, the in vitro culture time of CD19-directed CAR T cells was shortened from the traditional 9 or more days to 4 or 6 days, showing excellent anti-tumor efficacy.

Although encouraging, this strategy only shortens the time between leukemia treatment and infusion by a few days.

Patients still have to wait for the period of leukemia treatment and QC/QA testing after the end of production.


Intrinsic quality of T cells

The quality of leukemia products and subsequently isolated T cells plays an important role in determining the clinical response of treatment. When patients receive CAR T cell therapy, they have undergone countless lymphotoxic treatments, reducing their lymphocytes and having an optimal memory T cell subset pool to start making CAR T cells.

Research by researchers and other groups has shown that in CLL, MM and NHL, the presence and frequency of early memory CD8+ cells during leukocyte collection can highly accurately predict the efficacy of CAR T cell therapy, emphasizing the role of memory T cells in mediating The role of the reaction. In the GD2-CAR used to treat neuroblastoma, the persistence of CAR T cells has also been shown to depend on CD4+ memory.

Memory T cells essentially have increased proliferation and self-renewal capabilities. In the clinical phase III of CAR T cells, the relevant factor of clinical response is the degree of initial expansion and long-term persistence, which is the characteristic of memory T cells .

Therefore, to isolate the required cell population before manufacturing or to regulate the cell during the manufacturing process, whether it is genetic or pharmacological, to achieve the desired phenotype, continuous efforts are still needed.


CRS and neurotoxicity

The adaptive transfer of CAR-T cells is not without obvious and unique toxicity. In fact, the success of CAR-T cells is partially hindered by the severe side effects of cytokine release syndrome (CRS) and neurotoxicity, both of which lead to patient death.

CRS is a cytokine-mediated systemic inflammatory response, which is the result of CAR T cell activation and expansion.

A detailed overview of CRS, its causes, patient symptoms, clinical diagnosis and management can be found here.

CRS is a potentially life-threatening disease. If it is not treated, almost all clinical trials of bioactive CARs for hematological malignancies have been reported.

Therefore, it is worth considering CRS prevention strategies in the context of the next-generation general CAR design.


Universal donor CARs (UCAR) as a universal solution UCARs and allogeneic CARs

Another attractive approach to simplifying T cell manufacturing and facilitating easy availability is to produce universal “off-the-shelf” T cell products for use in cell therapy.

This strategy can simplify the entire process and significantly reduce manufacturing time, cost and effort. One of the main challenges of allogeneic CAR T cell therapy is to reduce the risk of graft-versus-host disease (GvHD), which is a potentially fatal medical difficulty, because in allogeneic transplantation, the graft recognizes the host as non-self through the TCR system , And attack the host.

Abnormality is also the reverse. The host may respond to UCAR T cells and limit their persistence, thereby limiting clinical efficacy.

This inherent mismatch can cause major problems for the efficacy of allogeneic CAR T cells by inhibiting expansion and persistence, and these two characteristics have been shown to be related to the persistence of response and remission.

In order to solve the problem of GvHD, researchers are using gene editing technology to target endogenous αβ TCR and MHC class I molecules to enhance the transplantation of T scientific researchers into recipients. Using a similar strategy, non-HLA-matched donor cells were transduced by lentivirus, and TALEN-mediated gene editing was performed on the TCRα chain and CD52 gene locus at the same time to obtain UCAR19T cells (UCART19).

They infused two infants with relapsed and refractory CD19+ B cell ALL with a single dose of UCART19 cells. These infants had received lymphatic regression chemotherapy and anti-CD52 serum therapy.

This preliminary trial reported that the two babies achieved molecular remission within 28 days, and the UCART19 cells continued to be regulated before the successful allogeneic stem cell transplantation.

In the phase I study of UCART19 in the treatment of children and adults with B-ALL, their patient population was expanded to 20 people, and the same group reported a sufficient expansion and a CR rate of 88%.

Surprisingly, only 15% of patients report severe CRS. Other UCARs designed by AllogeneTherapeutics are currently undergoing the first phase of investigation, such as Allo-501 for NHL and Allo-715 for MM.

Similar to UCART19, both drugs have TRAC and CD52 knocked out.

These preliminary results underscore the safety and effectiveness of this new product for the treatment of B-ALL and indicate that it is possible to greatly change the cost and accessibility of this revolutionary therapy.


Gene editing and UCART design to solve specific disease barriers

The emergence of the most advanced gene editing technologies, including zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and recently clustered regularly spaced short palindrome repeats (CRISPR)/CRISPR-associated9 (CRISPR/ Cas9), has paved the way for the production of highly specialized CAR T cell products with enhanced anti-tumor activity.

By using CRISPR/Cas9 technology, Eyquem et al. developed a strategy to knock CAR19 into the edited TRAC locus, thereby completing two cell engineering steps with one program to create a universal CAR. By placing CAR under the control of the endogenous TCR promoter, they reduced the tonic signal, delayed the differentiation after stimulation, and finally produced an anti-tumor effect in a mouse model of B-ALL. UCAR.

With the regulatory approval of this cell therapy in the United States and parts of the world, CAR-T cell therapy is expected to revolutionize cancer treatment. Looking back at the first-generation CAR, the proof of concept provided, to the follow-up research by adding costimulation domains to improve the design, and finally transformed into the clinical, it is obvious that this field is developing rapidly and has huge potential.

Now, combined with investment in basic immunology, advances in genome engineering, and important insights gained from countless phase I and phase II trials, the field of CAR-T cell therapy has transformed from a relatively unrefined manufacturing process to one that can generate the most effective T cells, and lower cost, thereby improving accessibility.

So far, through continuous technical improvement and strict clinical monitoring and management, the side effects of CAR-T have been effectively controlled.

The number of CAR-T treatments for cancer has gradually increased; CAR-T has been clinically used in leukemia, lymphoma and other blood diseases.

The performance is good, but there is a situation where targets are clustered in the field of hematology and tumors, most of which are arranged around CD19 targets. Therefore, how to choose different targets is a challenge for the future industry.

As solid tumor patients have redundant blood tumors, how to develop CAR-T therapies to deal with solid tumors is the future goal. Once breakthroughs are made, the industry will explode.



The next generation of CAR-T cells will overcome current shortcomings?

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