Surprise to win!

January 23, 2022/eMedClub News/--In 2021, a total of three CAR-T therapies will be approved for marketing by regulatory agencies such as the FDA and NMPA in the world
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The targets of currently marketed CAR-T therapies are highly concentrated on CD19, and only one newly approved Abecma is a BCMA target
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It also means that the current indications for hematological tumors are far ahead of the CAR-T solid tumor treatment
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The "dilemmas" of CAR-T in the treatment of solid tumors include: ➤ Lack of effective targets: Solid tumors have few surface tumor-specific antigens (TSAs), and many antigens are located inside
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At the same time, the currently discovered tumor-associated antigens (TAAs) are also expressed in normal tissues, which brings high off-target risks and safety issues
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➤ CAR-T transport and infiltration: Solid tumors have mechanisms to interfere with T cell transport for immune escape
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At the same time, solid tumors contain abundant tumor-associated fibroblasts and blood vessels, which form a physical barrier that hinders the entry of T cells
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In addition, the migration of T cells also depends on the chemokines secreted in the tumor microenvironment, but some solid tumors will inhibit their secretion, or secrete mismatched chemokines, resulting in low targeting and low killing of CAR-T cells ability
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➤ Immunosuppression of the tumor microenvironment: The tumor microenvironment (TME) has low pH, hypoxia, high permeability, and an immunosuppressive mechanism, which is extremely unfavorable for the survival and immune efficacy of T cells
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Recommended reading: Challenges and thoughts on CAR-T cell therapy for solid tumorsYimai Meng broke the news ➤ Endogenous T cell inhibitory signal: There is an endogenous regulatory mechanism for the immune activity of T cells.
When T cells are overactive, PD-1 and Molecules such as CTLA4 work to maintain immune balance
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After CAR-T cells are activated by antigens, PD-1 and CTLA4 bind to related ligands to inhibit the proliferation of T cells and the secretion of related cytokines, which reduces the antitumor activity of CAR-T
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Although TIL, TCR-T, CAR-M, NK/CAR-NK and other therapies with unique advantages are hot in the field of conquering solid tumors, there are still many developers and investors optimistic about CAR-T in the treatment of solid tumors.
track and find convertible directions through multiple angles
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This article will take stock of some of the CAR-T solid tumor therapies that have been publicly available in the past six months (if there are any omissions, please add them)
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(1) Development of novel antigen targets ➤ Just as CD19 is highly specifically expressed on B-cell hematological tumors, some specific solid tumors also have surface antigen receptors that are highly specifically expressed and suitable as tumor targets
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Mesothelin (MSLN) In December 2021, Atara Biotherapeutics announced its new CAR-T cell therapy ATA2271 targeting mesothelin (MSLN) at the 2021 European Society of Medical Oncology Immuno-Oncology (ESMO IO) Congress.
Preclinical and preliminary clinical results
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Recommended reading: Fighting solid tumors! Preliminary clinical results of next-generation CAR-T therapy are positiveYimai Meng revealed that mesothelin is a differentiation antigen that exists on normal mesothelial cells.
It is rarely expressed in normal tissues, but is present on the surface of aggressive solid tumor cells High expression, including mesothelioma, triple-negative breast cancer, esophageal cancer, pancreatic cancer and non-small cell lung cancer
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▲ MSLN is highly expressed in a variety of tumor tissues (source: PNAS) Claudin18.
2Claudin18.
2, a tight junction protein, is only expressed in differentiated epithelial cells on the gastric mucosa, and is not expressed in any other healthy tissues under normal circumstances
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However, it is highly expressed in primary malignancies such as gastric, breast, colon, and liver cancers, making it an ideal surface target for the treatment of such solid tumors
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▲ Expression of Claudin18.
2 in human normal tissues, primary gastric cancer tissues and metastases (Source: DOI: 10.
1093/jnci/djy134) In January 2022, Innovent registered IBI345 on the Clinicaltrials.
gov website The Phase I clinical trial plans to enroll 30 patients with Claudin18.
2 positive solid tumors
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The therapy is a CAR-T therapy targeting Claudin18.
2
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In November 2021, Keji Pharmaceutical announced that its Claudin18.
2-targeting autologous CAR-T (CT041) product candidate was approved for clinical trials in Canada, and also obtained the EMA priority drug qualification
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In September, Keji Pharmaceutical orally reported the latest progress of the Investigator-Initiated Trial (IIT) of this product candidate for the treatment of digestive system tumors at ESMO2021
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Recommended reading: Heavy! Keji Pharmaceutical's CLDN18.
2 autologous CAR-T drug candidate was approved for clinical trials in Canada.
In October 2021, Legend Bio held its first R&D day, in which LB1908 was introduced as an autologous CAR-T targeting Claudin18.
2 Immunotherapy, currently in Phase 1 clinical trials in China for the treatment of adult patients with advanced gastric cancer
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Legend Bio expects to submit an IND application to the FDA in the first half of 2022
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Follicle Stimulating Hormone Receptor (FSHR) In August 2021, Anixa Biosciences announced that its IND application for its autologous CAR-T therapy for ovarian cancer was approved by the FDA
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Recommended reading: Treating Ovarian Cancer! FDA approves autologous CAR-T targeting follicle-stimulating hormone receptor into the clinic Yimai Meng broke the news that the product uses CAR-T technology to target a protein receptor on the surface of ovarian cells called follicle-stimulating hormone receptor (FSHR)
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FSHR is only present on ovarian cells in adult women
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In addition, there is a hormone called follicle-stimulating hormone (FSH), which is tightly bound to FSHR
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This combination of hormone receptors has evolved over millions of years and is highly selective
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At the same time, FSHR appears to be expressed on the surface of blood vessels of other types of tumors, such as prostate, colon, lung, pancreas,
etc.

▲ FSHR also appears to be expressed on the surface of blood vessels in other types of tumors (Credit: DOI: 10.
1056/NEJMoa1001283) ➤ Some researchers have avoided the common pitfalls of CAR-T cell therapy by developing novel antigenic targets
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The limited efficacy in solid tumors is partly due to the depletion of CAR-T cells in the solid tumor microenvironment
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In November 2021, a paper titled "An NK-like CAR T cell transition in CAR T cell dysfunction" was published in Cell by the "Father of CAR-T" Carl June team, proving that genes downregulate the expressions of ID3 and SOX4 The efficacy of CAR-T cells in the treatment of solid tumors can be improved by preventing or delaying CAR-T depletion-induced dysfunction
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Recommended reading: "Father of CAR-T" Carl June discovers new targets that are expected to improve the efficacy of CAR-T in the treatment of solid tumors Research paper titled "Cross-HLA targeting of intracellular oncoproteins with peptide-centric CARs"
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The research team has developed a novel CAR-T cell therapy that eliminates tumors by targeting proteins within tumor cells that are critical for tumor growth and survival, experimenting in mouse models of neuroblastoma
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Recommended reading: Breakthrough progress! Next-generation CAR-T cell therapy is expected to overcome the problem of solid tumorsYimai Meng broke the news In July 2021, Genocea Biosciences announced that its innovative T cell therapy GEN-011 completed the first patient dosing in a 1/2a clinical trial (TiTAN) , focusing on patients who have failed standard checkpoint inhibitor therapy
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GEN-011 is a T-cell therapy candidate targeting individual neoantigens, derived from patient-specific neoantigen-activated peripheral blood T cells (NPTs), screened by Genocea's unique technology platform, ATLAS, and expanded to create custom of treatment
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Recommended reading: In the treatment of solid tumors, the first patient in another clinical study of neoantigen T-cell therapy has completed the dosingYimai Meng reveals that NPT has the least number of non-tumor-specific cells and excludes statins that may be detrimental to clinical response specific cells
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The screened GEN-011 is mainly composed of NPT CD4+ and CD8+ with broad neoantigen coverage, they are specific for up to 30 antigens and have a strong ability to limit tumor escape
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▲ Schematic diagram of CAR-T therapy for screening neoantigens (Source: Genocea) (2) Combination therapy ➤ Oncolytic virus combined with CAR-T is the most common combination therapy.
In January 2022, Boshengji and oncolytic virus were clinically developed The company Transgene announced a deep strategic cooperation agreement to evaluate the combination of Boshengji's TAA06-CAR-T cell injection and Transgene's intravenous Armed oncolytic virus in the treatment of malignant solid tumors such as pancreatic cancer and brain glioma feasibility and efficacy
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The goal of this collaboration is to explore the synergistic mechanism of CAR-T cells combined with oncolytic viruses to enhance therapeutic effects
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 The oncolytic virus developed by Transgene can specifically replicate in tumor cells and cause tumor cell lysis without affecting normal cells.
It can effectively release tumor antigens, recruit immune cells, and even have the potential to transform cold tumors into hot tumors
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Therefore, both parties agreed that combination therapy should be the preferred option to improve the solid tumor microenvironment and overcome tumor heterogeneity
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Recommended reading: Boshengji Pharmaceuticals and Transgene of France Work Together to Combine Oncolytic Virus and CAR-T Cell Therapy for Solid Tumors Imugene's CD19 oncolytic virus technology and Celularity's CD19 allogeneic CAR-T cell therapy CYCART-19 for the treatment of solid tumors
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Recommended reading: "Spot-type" CAR-T teamed up with oncolytic viruses to overcome the limitations of solid tumors Yimai Meng broke the news that this combination therapy aims to use oncolytic viruses armed with tumor antigens to infect tumor cells to express CD19, and then transfer tumor cells to tumor cells.
It is "marked" to help CD19 CAR-T cells target and eradicate solid tumors
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▲ Schematic diagram of oncolytic virus + CD19 CAR-T combination therapy (Source: Imugene) ➤ Other combination therapy In July 2021, BioNTech and Takara Bio signed a license and supply agreement for RetroNectin® technology
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RetroNectin® is a recombinant human fibronectin fragment containing three functional domains: cell binding domain, heparin binding domain and CS-1 sequence
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Recommended reading: BioNTech is also developing CAR-T cell therapy to attack solid tumors Yimai Meng broke the news that this reagent will improve the transfer of retroviral/lentiviral vectors to T cells by helping the co-localization of target cells and virus particles Gene transduction efficiency and contribute to efficient expansion of T cells
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▲ Schematic diagram of RetroNectin’s mechanism of action (Source: Takara) (3) Novel CAR structure ➤ The main regulatory purpose of many new CAR structures is to improve the safety and targeting of CAR-T therapy, reduce exhaustion and improve proliferation
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A single modified CAR structure often aims to achieve multi-angle optimization
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In December 2021, EXUMA Biotech announced the completion of a $41 million Series B2 financing to support further development of its autologous subcutaneous (SC) rPOC CAR-TaNK platform and ongoing clinical studies of its tumor metabolism modulating (TMR) CAR technology
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Recommended reading: Using the tumor microenvironment as a logic gate, a new type of CAR-T overcomes the difficulty of solid tumorsYimai Meng revealed that EXUMA's TMR CAR-T cells use logic-gated "AND gates" to make treatment safer
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The "AND" gate is designed to translate into an activation signal only in the presence of two triggers: an acidic tumor microenvironment (TME) and a target antigen
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Thus, even when the target antigen is present on normal tissue, TMR CAR-T cells remain closed and do not react with normal tissue expressing the target antigen
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▲ TMR CAR-T logic diagram (Source: EXUMA) In December 2021, Poseida Therapeutics announced that the FDA has approved its IND application for its allogeneic CAR-T cell therapy P-MUC1C-ALLO1 for multiple solid tumor indications
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The trial is expected to start in 2022
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The therapy is developed using the non-viral piggyBac DNA modification system, Poseida’s core technology for CAR-T therapy development, which can deliver CAR molecular genes to T cells, thereby producing stem memory T cells (TSCM) with a high proportion of stem memory T cells.
The ability of CAR-T products to increase the duration of therapeutic response may lead to slower generation of TEFF cells, thereby reducing toxicity
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Recommended reading: Non-viral "allogeneic" CAR-T therapy is about to enter the clinic, targeting multiple solid tumorsYimai Meng broke the news In the same month, Lyell announced that its CAR-T cell therapy LYL797 has been approved by the FDA IND.
in patients with non-small cell lung cancer, triple-negative breast cancer and other types of solid tumors expressing tyrosine kinase-like orphan receptor 1 (ROR1)
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The company aims to overexpress c-Jun in CAR-T cells through ex vivo gene reprogramming technology Gen-R to reduce exhaustion, and through ex vivo epigenetic reprogramming technology Epi-R, it also aims to generate long-lasting stem cell properties T cell population
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Recommended Reading: Solid Tumor CAR-T Breakthrough Again The CAR-T therapy for metastatic colorectal cancer received IND approval from the FDA, and a Phase 1 clinical trial will be launched in the first half of 2022
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The company received more than $40 million in Series C financing in September
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ICT's proprietary Solid Tumor CoupledCAR technology enables engineered CAR-T therapies to release cytokines that promote solid tumor CAR-T cell proliferation, tumor infiltration and target cell killing
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▲ Schematic diagram of the mechanism of action of CoupledCAR (Source: ICT) In October 2021, Leucid Bio announced the completion of about US$16 million in Series A financing to launch its CAR-T cell therapy LEU-011, which is under development for the treatment of platinum-based chemotherapy-resistant ovaries Phase 1 clinical trial in cancer
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Recommended reading: "Parallel" CAR-T is here! The new company raised 10 million US dollars to develop the next-generation tumor immunotherapy for solid tumorsYimai Meng broke the news that the company's CAR-T cell therapy is based on a novel CAR structure, called "parallel CAR" (pCAR) T cells, and at the same time Two CARs are expressed: one is a second-generation CAR with a single costimulatory domain; the other has a different costimulatory domain
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▲ A schematic diagram of the “parallel” CAR structure (Source: Leucid) In October 2021, AffyImmune Therapeutics announced the completion of a $30 million Series A financing to advance its Phase 1 clinical trial of its lead CAR-T cell therapy, which has not been treated yet.
Differentiated thyroid cancer and refractory poorly differentiated thyroid cancer
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AffyImmune's strategy is to reduce the affinity of the CAR
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Low-affinity CARs can efficiently bind to tumor cells with higher levels of antigen expression, while avoiding normal cells with low levels of antigen expression
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In addition, the low-affinity CAR activates CAR-T cells in a way more similar to the natural activation of T cells
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This type of activation can better maintain long-term tumor-killing efficacy, resulting in greater clinical benefit
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Recommended reading: Fine-tuning CAR-T affinity for solid tumors, cutting-edge $30 million Series A financingYimai Meng broke the news In September 2021, researchers at the Georgia Institute of Technology developed a new type of "photothermal" switch" CAR-T cell therapy
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The researchers added a photothermal-sensitive switch to CAR-T cells, so that these CAR-T cells could trigger the expression of CAR at 40-42 °C.
The study showed that after heating for 15-30 minutes, the transgene expression of these T cells exceeded 60-fold, improving CAR expression ability without affecting cell proliferation, migration and cytotoxicity
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Recommended reading: Nature Sub-issue: "Photothermal Switch" CAR-T Cells Precisely Target Solid Tumors The reference for reference has a good prospect of conversion
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However, some classic targets in the field of antibodies have problems such as low response rates in CAR-T therapy, and new breakthroughs need to be explored
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International companies currently deploying CAR-T therapy for solid tumors include Celyad, Mustang Bio, BMS, BioNTech, Belicum, Poseida, Atara,
etc.

Domestic companies include Keji Pharmaceutical, Sibeman, Gracell Bio, Innovent Bio, Reindeer Medical, Chongqing Precision Bio, etc.
(If there are any omissions, please add
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Further clinical translation and data validation are needed in this area
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