In recent years, chimeric antigen receptor (CAR) T cell therapy has made great achievements in the treatment of hematological tumors. In 2017 alone, the FDA approved the marketing of two CAR-T cell therapeutic products.

Extending this technology to solid tumors is a major challenge that scientists are striving to conquer in recent years. More and more clinical trials of CAR-T cell therapy for solid tumors have been carried out, for example, targeting gangliosides (GD2) for the treatment of neuroblastoma, targeting mesothelin for the treatment of pancreatic cancer, targeting carcinoembryonic antigen (CEA) for the treatment of colorectal adenocarcinoma, targeting fibroblast activation protein (FAP) for the treatment of malignant pleural mesothelioma, targeting epidermal growth factor receptor ( EGFR) for the treatment of non-small cell lung cancer, targeting delta-like protein 3 (DLL3) for the treatment of small cell lung cancer, targeting integrin-related protein (CD47) for the treatment of ovarian cancer and colorectal cancer.

However, the initial results of most clinical trials are not satisfactory, the effectiveness is far lower than CAR-T treatment of hematological tumors, and often accompanied by toxicity. Despite this, many researchers have long been committed to the transformation and optimization of CAR-T via ways of finding the best tumor targeting, maintaining the persistence of T cells in vivo and maintaining immune suppression against the tumor microenvironment, in a hope to incorporate more indications into the therapeutic range of this breakthrough technology.

All these measures adopted could be summarized as follows:

1. In pre-clinical trial phase

1. CAR-T cell therapy with PD-1
In August 2018, Eureka Therapeutics and MSK collaborated on the study of developing novel CAR-T cells, which was published in Nature Biotechnology. The newly designed CAR-T cells secrete a mini version of the checkpoint blocking antibody PD-1 that can activate T cells nearby to help fight the tumor.

2. Controllable CAR-T cell therapy
In August 2018, a study of a novel CAR-T cell developed by the University of New South Wales in Sydney and the University of California was published in Gut. The activity of this CAR-T cell is controlled by a tumor antigen-specific based on dose of Fab, thus providing a fully controllable immune response.

3. Dual-target CAR-T cell therapy for brain tumors
In September 2018, the EGFR/EGFRvIII dual-target CAR-T cell co-developed by Shanghai Jiaotong University School of Medicine and Koji Bio was published in Cancer Immunology Research. The team developed a humanized antibody M27, which specifically recognizes EGFR and EGFRvIII in glioblastoma cells at the same time to avoid toxic side effects caused by off-target.

4. Three-target CAR-T cell therapy for pancreatic cancer
In June 2018, a study of Baylor College of Medicine was published in Cancer Discovery. A novel CAR-T cell therapy (called SmarT-cell) that simultaneously targets three antigens (PSCA, TGF, and IL4), was discovered. As confirmed by preclinical studies, this therapy shows enhanced anti-tumor activity and selectivity with no side effects.

5. Super CAR-T that eliminates multiple solid tumors and prevents recurrence
In March 2018, a research led by Japanese scientist Koji Tamada was published in Nature Biotechnology. By transferring IL-7 and CCL19 genes into CAR-T cells, a super-CAR-T was created to effectively kill tumors. The cells (7×19 CAR-T) have an anti-tumor effect that is at least 4 times stronger than normal ones.

2. In clinical trial stage

1. Koji Bio’s CAR-Claudin 18.2 T cell treatment of gastric cancer and pancreatic cancer
In September 2018, Kozi Bio announced its clinical data on the treatment of gastric cancer/pancreatic cancer with CAR-Claudin 18.2 T cells. Of the 12 patients treated, 8 experienced varying degrees of tumor regression. In particular, in an improved treatment subgroup, according to the RECIST 1.1 standard, 5 out of 6 patients achieved objective remission (one of whom was confirmed to be objectively remission) and the other achieved complete remission.

2. Uric ET140202 ARTEMISTM T cell treatment of liver cancer
In September 2018, Uric released clinical data from its ET140202 ARTEMISTM T cell immunotherapy for patients with alpha-fetoprotein-positive advanced hepatocellular carcinoma, one of the most prevalent liver cancers. The results of the study showed that ET140202 T cell therapy did not cause any cytokine release syndrome (CRS) and drug-related neurotoxicity, indicating good safety. Three of the six subjects who had received treatment reached tumor regression. One of the advanced patients who received the drug by intravenous infusion was observed to have complete tumor regression after treatment.

3. Cell Medica's CAR-NKT cell therapy for neuroblastoma
In September 2018, Cell Medica announced that the world's first child neuroblastoma patient has successfully accepted the company's ongoing autologous CAR-NKT therapy CMD-501. CMD-501 (GD2-CAR NKT) targets GD2 and binds to the secretion of genetically engineered chimeric antigen receptors (CARs) and IL-15 cytokines to maintain therapeutic cell activity in an immunosuppressive tumor microenvironment.

4. Seattle Children's Hospital's innovative CAR-T therapy for sarcoma, kidney cancer and neuroblastoma
In August 2018, Seattle Children's Hospital announced the launch of an innovative CAR-T clinical trial (NCT03618381), STRIvE, for children and young patients with solid tumors that express EGFR protein in a relapsed or refractory non-central nervous system. The researchers used the EGFR806 antibody to arm CAR-T cells, hoping to selectively detect and destroy solid tumor cells expressing EGFR and limit their toxicity to normal tissues.

5. MSKCC CAR-T treatment of mesothelioma
In May 2018, MSKCC's CAR-T (targeted mesothelin MSLN) used a second-generation CD28 co-stimulation of MSLN CAR and an Icaspase-9 safety gene (IcasM28z) to treat mesothelioma. Clinical results showed that in 12 patients with malignant pleural disease, 6 patients were detected with CAR-T cells in peripheral blood, and 7 patients were treated with anti-PD-1 checkpoint inhibitor (Keytruda), and did not experience toxicity. A PET scan of one of the MPM patients showed complete remission, which remained clinically good 8 months after CAR-T cell infusion.

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 peptide nucleic acid, neoantigen peptides vaccine, checkpoint inhibitors, isotope labeled peptides, antimicrobial peptides, FRET substrates, glucagon like peptides, 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.