November 28, 2021

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Top 10 targets of CAR-T development for solid tumors

Top 10 targets of CAR-T development for solid tumors



Top 10 targets of CAR-T development for solid tumors.

Although CAR-T has amazing curative effects in hematological tumors, there are currently 5 products on the market. However, for solid tumors, the response rate is still very low based on the published clinical data.

This article briefly sorts out the current top 10 targets and clinical overview of CAR-T development for solid tumors (more than 60% of the total clinical number) for your reference.

Top 10 targets of CAR-T development for solid tumors.

Current Opinionin Pharmacology 2021, 59:70–84

1.  Mesothelin

Introduction

Mesothelin, overexpressed in various solid tumors and limited expression in healthy mesothelial cells, is an ideal TAA with low on-target and off-tumour toxicity.

Clinical overview

29 clinical trials can be retrieved, and solid tumors rank first. As shown in the figure above, the clinical efficacy of single treatment is limited, and the response rate does not exceed 25%.

2. GD2

Introduction

The expression of disialylganglioside GD2 in normal tissues is mainly restricted to the central nervous system, peripheral sensory nerve fibers, dermal melanocytes, lymphocytes and mesenchymal stem cells. The physiological functions of normal cells have not yet been fully elucidated. In cancer, GD2 helps to enhance tumor cell proliferation, movement, migration, adhesion and invasion, and resist apoptosis.

Clinical overview

26 clinical trials can be retrieved, ranking second. As shown in the table above, the clinical efficacy of monotherapy is limited.

3. HER2

Introduction

The carcinogenic potential of HER2 has been confirmed in a variety of human malignancies, especially breast cancer, gastric cancer, gastroesophageal junction cancer and so on. In these cancers, the main mechanism of HER2 activation is HER2 gene amplification, resulting in the complete overexpression of HER2 protein on the cell membrane. In addition, the genetic mutation of HER2 is also one of the key factors.

Clinical overview

26 clinical trials can also be retrieved. As a classic target, both antibody drugs and ADC drugs have achieved clinical breakthroughs, but CAR-T cell clinical trials have limited efficacy.

4. GPC3

Introduction

GPC3 is a 65kD protein composed of 580 amino acids. It is expressed in the liver and kidney of healthy fetuses, but is rarely expressed in adults, except for the placenta. But expressed in a variety of tumors, hepatocellular carcinoma (HCC), ovarian clear cell carcinoma, melanoma, lung cancer squamous cell carcinoma, hepatoblastoma, Wilms tumor (Wilms tumor), yolk sac tumor and some childhood cancers . GPC3 is a very ideal target for solid tumors. Based on this, a variety of immunotherapies (including CAR-T) are being developed.

Clinical overview

23 clinical trials can be retrieved.

Top 10 targets of CAR-T development for solid tumors.Front.Oncol. 9:248

Renji Hospital and Keji Pharmaceuticals published the results of clinical trials (NCT02395250, NCT03146234) in Clin Cancer Res in 2020. According to the Kaplan-Meier method, the overall survival rates of 13 patients were 3 years, 1 year and 6 months respectively. 10.5%, 42.0% and 50.3%. One patient with persistently stable disease survived 44.2 months later. The expansion of CAR-T cells is often positively correlated with tumor response.

Top 10 targets of CAR-T development for solid tumors.

5. Claudin18.2 (CLDN18.2)

Introduction

CLDN18.2 is a splice variant of the membrane epithelial tight junction protein Claudin18 (CLDN18), which has been identified as a promising targeted biomarker. The expression profile of CLDN18.2 in normal tissues is limited, and it is only expressed in the supramolecular complex tightly connected to the gastric mucosa.

After malignant transformation, the change of cell polarity leads to the exposure of CLDN18.2 epitope, which is suitable for targeted therapy. In addition to gastric cancer, CLDN18.2 is abnormally expressed in various primary tumors and metastatic cancers, including pancreatic cancer, biliary tract cancer, ovarian cancer and lung adenocarcinoma.

Clinical overview

10 clinical trials can be retrieved.

Cozi Pharmaceutical CT041 independent research and development in China initiated against late (unresectable or metastatic) gastric / gastroesophageal junction cancer and pancreatic cancer Ib / II clinical trial ( NCT04581473) , was launched in the United States for advanced (not resection or clinical trials of metastatic Ib) gastric or pancreatic test ( NCT04404595) .

The 2021 European Society of Medical Oncology Conference (2021 ESMO) gave an oral report. Among 36 patients with tumor target lesions, 31 patients observed varying degrees of target lesion reduction, and the overall objective response rate (ORR) was 48.6%. Disease control The DCR is 73.0%.

6. CEA

Introduction

Carcinoembryonic antigen (CEA) is a tumor-associated antigen first extracted from colon cancer and embryonic tissues by Gold and Freedman in 1965. It is a broad-spectrum tumor marker. In theory, CEA CAR-T has a broad-spectrum anti-cancer effect.

Clinical overview

Ten clinical trials can be retrieved, and clinical trials of single treatment showed limited efficacy.

NCT02416466,CAR-T Hepatic Artery Infusionsand Sir-Spheres for Liver Metastases (HITM-SIR),RogerWilliams Medical Center.

Top 10 targets of CAR-T development for solid tumors.

NCT02349724,AClinical Research of CAR T Cells Targeting CEA Positive Cancer,Southwest Hospital, China

Top 10 targets of CAR-T development for solid tumors.

7. EGFRvIII

Introduction

EGFRvIII is the most common mutation of EGFR. It does not exist in normal tissues and occurs in 25-64% of glioblastomas. EGFRvIII enhances tumorigenesis, increases tumor cell motility, and develops resistance to chemotherapy.

Clinical overview

11 clinical items can be retrieved, 2 of which are registered by Gary Archer Ph.D., Duke University (NCT03283631, NCT02664363), because the funding has been terminated. NCT02209376 was terminated and changed to combination therapy. There are currently 8 clinical trials in progress.

NCT01454596 conducted by Steven Rosenberg, MD of the National Cancer Institute (NCI), the results were published, the patient basically did not respond.

8. PSMA

Introduction

Prostate-specific membrane antigen (PSMA) is a type II membrane glycoprotein, which has been studied in the field of prostate cancer as a tumor-associated antigen for prostate cancer for 30 years.

Clinical overview

There are currently 10 clinical trials registered, of which 6 are from the Shenzhen Institute of Immunogene Therapy. At present, there is no public literature that publishes relevant clinical data.

CAR-T boss Carl H. June registered NCT03089203 (CART-PSMA-TGFβRDN Cells for Castrate-Resistant Prostate Cancer) based on previous research. In its pre-clinical research paper, it was commented that the clinical study conducted by MemorialSloan Kettering Cancer Center (NCT01140373) ” Since 2010, the anti-PSMA CART has limited durability and no patient response has been observed” (Ref. 6).

CART-PSMA-TGFβRDN mouse model data (Reference 6)

9. EGFR

Introduction

EGFR is a type I transmembrane protein with cytoplasmic tyrosine kinase activity. It belongs to the HER/ErbB family. It is overexpressed in about 40-89% of NSCLC and plays an important role in the progression of NSCLC. In addition, EGFR is also highly expressed in malignant solid tumors such as pancreatic cancer.

Clinical overview

There are 10 clinical registrations, showing a certain clinical effect.

NCT03182816 CTLA-4 andPD-1 Antibodies Expressing EGFR-CAR-T Cells for EGFR Positive Advanced SolidTumor, Shanghai Institute of Cell Therapy. Results: 9 patients, 1 PR, 6 SD, 2 PD. (Document 7)

NCT01869166, Treatment of Chemotherapy RefractoryEGFR (Epidermal Growth Factor Receptor) Positive Advanced Solid Tumors (CART-EGFR) (CART-EGFR), Professor Han Weidong, General Hospital of PLA. (Document 8)

Results: 16 patients, 4 PR, 8 SD.

10. EpCAM

Introduction

Epithelial cell adhesion molecule (Epithelial cell adhesion molecul, EpCAM) is a transmembrane glycoprotein, which is mainly expressed in order and direction on some luminal epithelial cells. After malignant transformation, EpCAM is overexpressed in an unrestricted pattern on some cancer cells.

Clinical overview

There are currently 9 clinical registrations from West China Hospital, the Second Anhui Provincial Hospital, and the First Hospital of Anhui Medical University.

Currently, there is no publicly published data.


Summary

Solid tumor CAR-T currently has about 40 targets in clinical trials, of which the top 10 targets account for more than 60% of the total clinical number. From the current clinical data, no good clinical response has been observed for classic targets such as HER2 and GD2, and targets such as Claudin18 and GPC3 have shown a certain clinical response.

Several major problems faced by CAR-T for solid tumors, such as difficulty in local tumor invasion, poor durability, and low survival of the tumor microenvironment, still restrict the clinical development of CAR-T in solid tumors.

In recent years, genetic engineering of cytokines into CAR-T to increase durability, viability, and function; removal of immune checkpoints through gene editing; and the use of tumor infiltrating lymphocytes (TIL), etc., have made some progress, but still need Tested in clinical trials.

references:

1.Victor Moreno et al,Adoptive cell therapy for solid tumors:Chimeric antigen receptor T cells and beyond,CurrentOpinion in Pharmacology 2021, 59:70–84
2.Mount, C. W. et al. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas. Nat. Med.24,572–579 (2018).
3.Shimizu Y, Suzuki T, YoshikawaT, Endo I and Nakatsura T (2019) Next-Generation Cancer Immunotherapy TargetingGlypican-3. Front. Oncol. 9:248
4. DonghuaShi et al,ChimericAntigen Receptor-Glypican-3 T-Cell Therapy for Advanced HepatocellularCarcinoma: Results of Phase I Trials,Clin Cancer Res .2020 Aug 1;26(15):3979-3989.
5. StevenC. Katz et al,HITM-SIR:phase Ib trial of intraarterial chimeric antigen receptor T-cell therapy andselective internal radiation therapy for CEA+ liver metastases,Cancer Gene Therapy https://doi.org/10.1038/s41417-019-0104-z
6. ChengchengZhang et al,Phase IEscalating-Dose Trial of CAR-T Therapy Targeting CEA+ Metastatic ColorectalCancers, Molecular Therapy Vol. 25 No 5 May 2017
7. ChristopherC. Kloss et al,Dominant-NegativeTGF-b Receptor Enhances PSMA-Targeted Human CAR T Cell Proliferation AndAugments Prostate Cancer Eradication,Molecular TherapyVol. 26 No 7 July 2018
8. YajunZhang et al,Phase Iclinical trial of EGFR‑specifcCAR‑T cells generated by thepiggyBac transposon system in advanced relapsed/refractory non‑small cell lung cancer patients,Journal of Cancer Researchand Clinical Oncology https://doi.org/10.1007/s00432-021-03613-7
9. YangLiu et al,Anti-EGFRchimeric antigen receptor-modified T cells in metastatic pancreatic carcinoma:A phase I clinical trial,Cytotherapy 22 (2020) 573-580

Top 10 targets of CAR-T development for solid tumors.

(source:internet, reference only)


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