Anti-cancer weapon: CAR-T cell therapy

Anti-cancer weapon: CAR-T cell therapy, the latest progress!

Anti-cancer weapon: CAR-T cell therapy. CAR-T (Chimeric Antigen Receptor T-Cell Immunotherapy), namely chimeric antigen receptor T-Cell Immunotherapy. This therapy is a new type of cell therapy that has appeared for many years but has only been improved and used in the clinic in recent years. It has significant efficacy in the treatment of acute leukemia and non-Hodgkin’s lymphoma, and is considered to be one of the most promising tumor treatment methods. Like all technologies, CAR-T technology has undergone a long evolutionary process. It is during this series of evolutionary processes that CAR-T technology gradually matures.

The key to this new treatment strategy is the artificial receptor called chimeric antigen receptor (CAR) that recognizes target cells, and after genetic modification, patient T cells can express this CAR . In human clinical trials, scientists extract some T cells from patients through a process similar to dialysis, and then genetically modify them in the laboratory to introduce the gene encoding this CAR so that these T cells can express This new receptor. These genetically modified T cells are proliferated in the laboratory and then infused back into the patient. These T cells use the CAR receptors they express to bind to molecules on the surface of target cells, and this binding triggers the generation of an internal signal, which then activates these T cells so strongly that they quickly destroy the target cell.
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In recent years, CAR-T immunotherapy has been used to treat acute leukemia and non-Hodgkin’s lymphoma. After improvements, it has also been used to treat solid tumors, autoimmune diseases, HIV infection and heart disease. Broader application space. Based on this, the editor will take stock of the latest progress in CAR-T cell therapy for readers.

1. Science and Cell sub-journals: Develop “smart” cell therapies to treat cancer with the help of big data
doi:10.1016/j.cels.2020.08.002; doi:10.1126/science.abc6270

Finding drugs that can kill cancer cells and protect normal tissues is the highest goal of oncology research. In two new papers, researchers from the University of California, San Francisco and Princeton University proposed a complementary strategy to use “smart” cell therapy to solve this problem: unless it is only found in a group of cancer cells at the same time The protein is activated, otherwise these living cell drugs will remain inert.

The biological aspects of this general method have been explored for several years in the laboratory of Dr. Wendell Lim and his colleagues in the Cell Design Program at the University of California, San Francisco and the Center for Synthetic Immunology sponsored by the National Cancer Institute. However, their new research adds a powerful new dimension to this by combining cutting-edge therapeutic cell engineering with advanced computational methods.

In the first paper titled “Discriminatory Power of Combinatorial Antigen Recognition in Cancer T Cell Therapies” published in the journal Cell Systems on September 23, 2020, members of the Lim Lab collaborated with Princeton University’s Louis-Sigler The research team of Dr. Olga G. Troyanskaya, a computer scientist at the Institute of Genomics, joined forces. Using machine learning methods, they analyzed a massive database of thousands of proteins found in cancer and normal cells. Subsequently, they screened millions of possible protein combinations to construct a catalog of protein combinations that can be used to precisely target cancer cells, not normal cells.

Image source: Cell Systems, 2020, doi:10.1016/j.cels.2020.08.002

In the second paper titled “Precise T cell recognition programs designed by transcriptionally linking multiple receptors” published in Science on November 27, 2020, Lim and colleagues then showed how to calculate these The resulting protein data is used to promote the design of effective and highly selective cancer cell therapies.

2. Science Sub-Journal: Clinical trials show that CAR-T cells targeting GD2 are expected to treat neuroblastoma
doi:10.1126/scitranslmed.abd6169

In a new study, researchers from research institutions such as Great Ormond Street Children’s Hospital and University College London have developed a new type of CAR-T cell therapy designed to target cancerous tumors. Children with blastoma, a rare childhood cancer, show promising early results. The relevant research results were published in the journal Science Translational Medicine on November 25, 2020. The title of the paper is “Antitumor activity without on-target off-tumor toxicity of GD2–chimeric antigen receptor T cells in patients with neuroblastoma”.

In this proof-of-principle study, these authors genetically modified the patient’s own T cells (a type of immune cell) to have the ability to recognize and kill neuroblastoma cells. Twelve children with relapsed or refractory neuroblastoma received this treatment as part of a phase I clinical trial funded by Cancer Research UK.

This study is one of the first studies to prove that CAR-T cells achieve rapid regression of solid cancer. Although the beneficial effects only lasted for a short time, it provides important evidence that this special CAR-T cell therapy can be used as a future treatment for solid cancer in children.

3. The new purification method is expected to reduce the manufacturing cost and side effects of CAR-T cells
News source: New approach to fighting cancer could reduce costs and side effects

Mona Elsemary, a PhD student at the Institute of Future Industries, University of South Australia, Australia, developed a microfluidic method to purify chimeric antigen receptor (CAR) T cells (CAR-T). CAR-T cells are genetically modified T cells and the basis of breakthrough cellular immunotherapy. CAR-T cell therapy is a transformative immunotherapy that uses the power of the patient’s immune system to fight cancer.

Elsemary said, “CAR-T cell therapy has achieved some remarkable results in the treatment of blood cancer. At present, a large number of international studies are working to translate this success into CAR-T cell therapy for solid cancer. However, CAR-T manufacturing There are still major obstacles and high costs to the process, which prevent the full potential of this life-saving therapy from being realized. “These problems include the presence of inactive cells and cell debris in cell preparations, as well as the freezing and storage of CAR-T cell products that are commonly used. Cryoprotectants (such as dimethyl sulfoxide).

This microfluidic method was developed by Professor Benjamin Thierry of the University of South Australia and his team in collaboration with Associate Professor Benjamin Thierry of the University of Technology, Sydney. It can remove more than 70% of the dead cells in CAR-T cell products within 30 minutes and make the cells viable. An average increase of 20%. In addition, more than 90% of the cryoprotectant dimethyl sulfoxide has been removed – all of which will not adversely affect the quality and function of these cells.

4. Interpretation of Cancer Cell review articles! How to engineer CAR-T cells to develop a new generation of cancer therapies?
doi:10.1016/j.ccell.2020.07.005

A few days ago, in a review article entitled “Engineering CAR-T Cells for Next-Generation Cancer Therapy” published in the international journal Cancer Cell, scientists from the University of California and other institutions discussed how to engineer CAR-T cells Modified for use as a new generation of cancer therapy.

T cells that have been engineered to express tumor-specific chimeric antigen receptors (CARs) have achieved remarkable curative effects in the treatment of patients with malignant hematological tumors, and also brought to the research field of adoptive cell therapy A revolutionary breakthrough, however, to achieve a wider range of therapeutic applications of CAR-T cells requires a multi-level engineering approach to improve the efficacy and safety of treatment, especially due to the biological effects of the tumor microenvironment (TME) Complexity often brings unique challenges to its treatment. In this review article, researchers discussed how to improve the interactions between CAR proteins, T cells, T cells and other components in TME The latest strategy of CAR-T cell therapy.

In the article, the researchers discussed from the following aspects:

• 1) The evolutionary history of CAR design;
• 2) Combined antigen activation for logic gated T cell activation;
• 3) The controllability and safety of the on/off switch;
• 4) Adapter-dependent CARs;
• 5) Safety control of CAR-T cell activity;
• 6) Regulating the expression of CAR is used to improve the safety of CAR-T cells;
• 7) Site-specific CAR transgene insertion and allogeneic compatible engineering modification;
• 8) Promote the transgene expression of T cell function;
• 9) Autocrine stimulation of CAR-T cells in the tumor microenvironment;
• 10) Homing and penetration of tumors;
• 11) Destruction of the immunosuppressive axis;
• 12) Reshape the tumor microenvironment to promote the endogenous immune response.

5. New research shows that it seems safe for patients with multiple myeloma to receive radiotherapy before receiving CAR-T cell therapy and will not affect the efficacy of CAR-T cells
News source: Penn Study supports use of radiation before CAR therapy for multiple myeloma

In a new study, researchers from the Abramson Cancer Center at the University of Pennsylvania in the United States found that it is safe to give radiotherapy to patients with multiple myeloma waiting to be made by CAR-T cells and will not damage CAR- T cell therapy. The relevant research results will be presented at the virtual annual meeting of the American Society of Radiation Oncology on October 27, 2020.

This study found that in patients who received radiotherapy 34 days before or less than the infusion of BCMA CAR-T cells (CAR-T cells targeting the BCMA antigen), their severe cytokine release syndrome (CRS) The incidence of neurotoxicity (two common side effects of cell therapy) and hematological toxicity is not worse than that of patients who have not received radiotherapy.

This study is a retrospective analysis of a collaborative project between the Abramson Cancer Center of the University of Pennsylvania and Novartis. It evaluated the medical records of 25 patients receiving BCMA CAR-T cell therapy and divided them into three groups. A group of patients received radiotherapy 34 days or less after their T cells were collected for BCMA CAR-T cell production, but before the infusion of these BCMA CAR-T cells. The second group of patients had received radiotherapy within one year before the BCMA CAR-T cell infusion. The third group of patients did not receive radiotherapy within one year before the BCMA CAR-T cell infusion.

Among the 4 patients who received radiotherapy while waiting for the production of BCMA CAR-T cells, none of them had CRS higher than grade 3, gastrointestinal, infectious, liver-related or neurotoxic side effects. CRS is a side effect, including flu-like symptoms of varying degrees, accompanied by high fever, nausea, and muscle pain, and may require intensive care. The incidence of grade 4 blood toxic side effects in these patients is also low. Of the 8 patients who had a history of radiotherapy, 3 had CRS grade 3 or higher. Of the 13 patients who did not receive any radiotherapy, 5 had CRS grade 3 or higher. Radiotherapy status has nothing to do with the decline in overall survival or progression-free survival.

6. JEM: New research improves the detection sensitivity of CAR-T targeted therapy
doi:10.1084/jem.20192203

In a recent study, Ludwig Cancer Research scientists have developed a method that can significantly improve the preclinical evaluation of chimeric antigen receptor (CAR) T cell therapy, which is to extract immunity from patients The system’s T cells are designed to target specific tumor-related molecules, and then grow and reinject to treat cancer. The study was published in the Journal of Experimental Medicine. The study also reported the construction and evaluation of a co-designed CAR-T cell, and applied this method to examine its effect on tumors in a mouse model of skin cancer and melanoma .

Although CAR-T therapy has been approved for blood cancer, its application to solid tumors has proved to be challenging. Part of the reason is that the complex microenvironment of solid tumors suppresses the immune response in many ways.

“Most of the research on CAR-T therapy is done in mice lacking their own immune system, because if these mice have a normal immune system, it will attack human CAR-T cells,” said researcher Melita Irving Luther The Vichy Cancer Institute Lausanne and Ludwig Lausanne Director George Coukos co-led the research. “But the tumor microenvironment may have a huge impact on T cell products, so we hope to use engineered mouse T cells in mice with strong immunity for research. This allows us to simultaneously observe the immune system and CAR-T cells. “

They showed that CAR-T cells cultured using this method are significantly activated after exposure to their target. These cells also show signs of being younger and have molecular characteristics shared by memory T cells. When stimulated by a target, they grow rapidly.

7. Science Sub-Journal: Continuous activation of transcription factor STAT5 can improve the anti-tumor immune response of CAR-T cells
doi:10.1126/sciimmunol.aba5962

Adoptive cell therapy using chimeric antigen receptor (CAR) T cells (CAR-T) has shown strong anti-tumor immunity, but T cell failure may impair their efficacy. The existence of multifunctional CD4+ T cells is usually associated with good anti-tumor immunity. Scientists have previously found that IL-7 treatment can induce the activation of multifunctional CD4+ T cells that produce multiple cytokines.

In a new study, researchers from research institutions such as Augusta University in the United States reported that the continuous activation of the transcription factor STAT5 in tumor-specific CD4 + T cells drives the production of multifunctional T cells. The relevant research results were published in the journal Science Immunology on October 30, 2020, with the title of the paper “Persistent STAT5 activation reprograms the epigenetic landscape in CD4+ T cells to drive polyfunctionality and antitumor immunity”.

They found that the ectopic expression of the constitutively active form of murine STAT5A (CASTAT5) of murine STAT5A enables the robust expansion of tumor-specific CD4 + T cells, which infiltrate tumors effectively, and in CD4 + T cell adoptive transfer model system triggers anti-tumor CD8 + T cell response.

Comprehensive epigenomics and transcriptomics analysis showed that CASTAT5 induced genome-wide chromatin remodeling in CD4 + T cells, and established a unique epigenetics and transcription landscape. Single-cell RNA sequencing analysis further identified a subpopulation of CD4 + T cells transduced by CASTAT5, which has molecular characteristics indicative of progenitor polyfunctional T cells.

These researchers found that in a mouse B-cell lymphoma model, adoptive transfer of T cells that co-express CASTAT5 and CD19-targeted chimeric antigen receptor (CAR) after modification resulted in the production of multifunctional CD4 + CAR-T cells . This discovery makes CASTAT5 potentially therapeutic.

8. Nat Med: Phase I clinical trials show that bispecific CD19/CD20 CAR-T cells are expected to treat recurrent B-cell malignancies
doi:10.1038/s41591-020-1081-3

Chimeric antigen receptor (CAR) T cell (CAR-T) therapy is considered a breakthrough technology for the treatment of multiple types of tumors. Non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) are two CD19-positive B-cell cancers that have been treated with CAR-T cells that recognize CD19. Although CD19 is a classic molecule located on the surface of B cells, methods that target CD19 alone to down-regulate its expression often encounter treatment failures.

To overcome this limitation, Shah et al. used an automated cell processing platform in a new study to develop CAR-T cells that target CD19 and CD20 (hereinafter referred to as CD19/CD20 CAR-T cells). therapy.

This study is a phase 1 dose escalation and expansion clinical trial. In this clinical trial, these bispecific CAR-T cells are used to treat patients with NHL or CLL. Based on this, this clinical study included 26 patients who had previously experienced multiple anti-B cell treatments and failed. In general, this bispecific CAR-T cell therapy is considered to be therapeutically safe. 64% and 32% of patients had cytokine release syndrome and neurotoxicity, respectively. The overall response rate was 82%, and all 12 patients who received high-dose, freshly prepared CD19/CD20 CAR-T cells responded. In contrast, 43% of patients receiving cryopreserved CD19/CD20 CAR-T cells experienced treatment failure. This indicates that the use of freshly prepared CD19/CD20 CAR-T cells may be the key to successful treatment. Finally, 3 patients did not respond to this treatment. All non-responders showed high levels of circulating CAR-T cells, which suggested the presence of antigen stimulation, but the killing activity of these CAR-T cells was significantly reduced.

9. Heavy! Scientists have successfully produced new CAR-NKT cells or are expected to develop new immunotherapies to treat solid tumors
doi:10.1038/s41591-020-1074-2

Natural killer T cells (NKT) are a type of immune cells that have been shown to have potential anti-cancer properties in murine tumor models. Now researchers are expected to use NKT cells to develop a new type of immunotherapy to treat cancer patients. Recently, in a research report entitled “Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma: an interim analysis” published in the international journal Nature Medicine, scientists from Baylor College of Medicine and other institutions used research and use Chimeric antigen receptor (CAR) genetically modifies human NKT cells to specifically recognize and attack neuroblastoma (a childhood cancer). The modified NKT can express interleukin-15 (IL-15). ), which is a natural protein that can support the survival of NKT cells.

In this study, the researchers announced the interim results of an ongoing clinical trial. The results showed that the modified NKT cells are safe and can colonize tumors. Of the three patients tested, one The patient’s body successfully induced an objective response in addition to the degeneration of bone metastases. The earliest CAR modified cells are immune T cells. CAR T cells have been shown to be effective in treating leukemia and lymphoma. However, scientists have encountered some challenges in the process of trying to use CAR T cells to treat solid tumors. The results of preclinical studies show that NKT cells can provide a new way to help enhance CAR-directed cancer immunotherapy.

Researcher Professor Leonid Metelitsa said that in addition to effectively defending against tumors in mouse models, the presence of NKT cells in solid tumors is directly related to the favorable results of cancer patients. Previous research results have shown that NKT cells have broad-spectrum anti-tumor activities. For example, these cells can migrate to tumor sites, where they can kill tumor-related macrophages, etc., and macrophages are a type that can promote tumor growth and The transferred immune cells, in addition, the activation of NKT cells can indirectly promote the anti-tumor immune response mediated by NK cells and T cells.

10. elife: T cell anti-cancer new mechanism
doi:10.7554/eLife.56554

A new study published in the journal eLife shows that when T cells in the immune system find and recognize a target, they release chemicals to attract more T cells, and then gather to help suppress this threat.

The discovery of this grouping behavior, as well as the chemoattractants used by T cells to attract more T cells to tumors, could one day help scientists develop new cancer therapies that can boost the immune system. This is especially important for solid tumors. So far, solid tumors have a lower response to current immunotherapy than blood cancers.

The research team used 3-D tumor models grown in laboratories and mouse models to show that cancer-killing T cells can reside in tumor cells independently of intermediate immune cells. When T cells find and recognize a tumor, they release chemical signals, and then attract more T cells to sense the signal through a receptor called CCR5, and cause a cluster response. Galeano Niño said: “These cells coordinate their migration process, reminding people of the grouping behavior observed in certain insects and another group of immune cells called neutrophils, which help the body to deal with damage. To react with pathogens.”

After using computer models to confirm their results, the team genetically engineered human cells, called chimeric antigen receptor (CAR)-T cells, and proved that they also flock to the 3-D glial grown in the laboratory Blastoma tumor. CAR-T cells are currently being used to treat certain types of blood cancers. But the new findings indicate that it is also possible to train these cells to attack solid tumors.

11.Nature Cancer: Immunotherapy can treat rare eye cancers
doi:10.1038/s43018-020-00119-y

In a recent article, researchers found that a combination of CAR-T cells and immune-enhancing drugs packaged in an injectable gel can save the vision of mice implanted with human retinoblastoma tissue . On October 12, 2020, “Nature Cancer” magazine published the results of a study by scientists at the University of North Carolina Lineberger University Comprehensive Cancer Center.

First, the researchers tried chimeric antigen receptor-T (CAR-T) cell therapy, which is an immunotherapy in which T cells containing the immune system are modified in the laboratory to express proteins that target cancer surface Chimeric antigen receptor CARs. In laboratory tests, they found that a molecule GD2 is expressed in retinoblastoma, but the possibility of targeting this molecule to safely eliminate tumors in the eye is unclear.

Next, in order to test the safety and benefits of targeting GD2, the researchers injected CAR-T that recognizes the molecule into the retina of mice implanted with retinoblastoma cancer cells, and found that the therapy delayed tumor development. But it did not eradicate the tumor. Then, they combined CAR-T with interleukin (IL)-15 (a protein that can boost immune responses) and found that 60% of the mice were tumor-free for up to 70 days.

Finally, they injected a water-based gel containing CAR-Ts and IL-15 into the retina of mice. CAR-T and IL-15 retain the ability to attack cancer cells, control tumor growth and prevent tumor recurrence. They confirmed the restriction of tumor growth through several imaging examinations of the retina.

12. Nat Med: Characteristics of CAR-T cell therapy for patients with large B-cell lymphoma
doi:10.1038/s41591-020-1061-7

Recently, researchers at the University of Texas MD Anderson Cancer Center have determined the relevant molecular and cellular characteristics of CD19 CAR T cell therapy, which are related to the response of large B-cell lymphoma (LBCL) patients after treatment and whether they have side effects related. The research team also found that early changes in circulating tumor DNA after one week of CAR T cell therapy may predict the response of specific patients to treatment. The paper was published in the journal Nature Medicine.

This study shows that within the first week of treatment, clinicians may be able to identify some patients who may have worse outcomes or adverse treatment reactions. This will allow the care team to adjust the therapy to improve efficacy or reduce toxicity.

For this study, the researchers performed single-cell analysis of CAR T cells to study the gene expression profile injected into the cells. After treating 24 LBCL patients, CAR T cells were collected from the remaining cells in the infusion bag. These genetic profiles were compared with the treatment response determined by PET/CT scan three months after the infusion.

“When we observed the characteristics of the injected CAR T cells, we found that the T cells in the samples of patients who responded poorly to the treatment had been exhausted, while the T cells in the samples of patients who had fully recovered expressed’memory’ signals.” Author Sattva Neelapu, MD, professor of lymphoma and myeloma, said: “In addition, the cellular feature of T cell failure is more common in patients with poor performance, and poor molecular response is usually associated with lower positive long-term The results are relevant.”

13. Nat Immunol: The transcription factor BATF3 improves CD8+ T cell survival and immune memory
doi:10.1038/s41590-020-0786-2

Professors Wolfgang Kastenmueller and Professor Georg Gasteiger of the Institute of Systemic Immunology, University of Würzburg, Germany, focus on the interaction between the immune system and the body, especially the interaction of different cells of the immune system in the local network and with other organ systems The interaction between the cells.

In a new study, Kastenmueller and his team have deciphered new details about how the immune system functions. These details are important for the immune system to remember recent infections. The relevant research results were published online in the journal Nature Immunology on September 28, 2020. The title of the paper is “BATF3 programs CD8+ T cell memory”. Their findings may help improve immunotherapy for tumor diseases.

Image source: Nature Immunology, 2020, doi:10.1038/s41590-020-0786-2

Kastenmueller introduced the main results of his study, “In this study, we identified a transcription factor—BATF3, which very specifically regulates the survival of these cells and their conversion to memory response.” These studies The researchers confirmed that this transcription factor is only produced shortly after the initial activation of T cells. The lack of this transcription factor can lead to permanent failure of the memory response.

Prior to this, the effect of this transcription factor on so-called CD8+ T cells was unclear. Only after these researchers overexpressed this transcription factor in CD8+ T cells, its importance became clear, because they could observe that these cells survived, resulting in a significant improvement in immune memory.

This research combines basic research with applied medicine and may help to use the patient’s immune system to develop better cancer treatments, such as the so-called CAR-T cell therapy.

(source:yaochuanke)

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