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By Jacqueline Carrico, BS, MD Candidate
Developing successful CAR-T therapy requires identification of specific tumor-associated antigens, as the primary target for CAR-T binding and activation. Some solid tumors have well-characterized oncogenes which play a pivotal role in tumor cell proliferation, migration, and survival. These oncogenes are ideal targets for CAR-T therapy, particularly when the oncogene is expressed at low levels in normal tissues.
The tyrosine kinase receptor EGFR, is aberrantly expressed in non-small cell lung cancer (NSCLC), pancreatic cancer, head and neck squamous cell carcinoma, glioblastoma, and other malignancies. One variant known as EGFRvIII is an ideal target given that it is a known oncogene in glioblastoma multiforme (GBM) and is not expressed in normal tissues. Preliminary studies showed a reduction in tumor growth, increased survival time, and no toxicity to normal tissues in a murine GBM tumor model. Most notably, the studies proved that anti-EGFR CAR-T cells successfully crossed the blood brain barrier. A phase I clinical trial for NSCLC, showed that this therapeutic approach was both safe and feasible, with only minor and controllable toxicities and no reports of cytokine storm, an emerging concern in CAR-T therapy.
Immunohistochemistry-Paraffin: ErbB2/Her2 Antibody [NBP2-29624] - IHC analysis of a formalin-fixed paraffin-embedded (FFPE) human breast carcinoma tissue section using 1:50 dilution of ErbB2/HER2 antibody (NBP2-29624) on a Bond Rx autostainer (Leica Biosystems). The assay involved 20 minutes of heat induced antigen retrieval (HIER) with 10mM sodium citrate buffer (pH 6.0) and endogenous peroxidase quenching using peroxide block. The sections were incubated with primary antibody for 30 minutes. Bond Polymer Refine Detection (Leica Biosystems) and DAB were used for signal detection which followed counterstaining with hematoxylin. Whole slide scanning and capturing of representative images (20X) were performed using Aperio AT2 (Leica Biosystems). This ErbB3 antibody generated a diffused cytoplasmic with some membrane and nuclear staining in the cancer cells, endothelial cells as well as in the tumor stromal cells. The cells in the cores of some tumor areas were negative for ErbB2.
HER2 is a member of the EGFR family, which is overexpressed in many breast cancers. Currently monoclonal antibodies and tyrosine kinase inhibitors (TKI) are used to target HER2; however, the development of secondary resistance is very common in these approaches. A novel approach is tandem CAR-T therapy, in which the engineered T-cells express dual chimeric-antigen receptors for two different tumor surface markers. One study of tandem CAR-T cells targeting both HER2 and IL13Ra2 in breast cancer demonstrated a significant improvement in CAR-T function and cytokine release, as compared to traditional anti-HER2 CAR-T cells. This approach is particularly helpful for tumor models in which there is low expression of the target protein, a situation in which monoclonal antibodies and TKI’s are ineffective.
MSLN is an oncogenic protein found in mesothelioma, ovarian carcinoma, and pancreatic adenocarcinoma. In ovarian cancer, overexpression of the folate receptor was found to be a prominent feature of malignant cells. Therefore, tandem CAR-T cells targeting both MSLN and the folate receptor were developed and showed potent antitumor activity with minimal toxicity. This approach helps to increase specificity of the CAR-T therapy for malignant cells while minimizing the effect on normal tissues. Given the high levels of MSLN expression in many normal tissues, modifying this therapy will be important to avoid potentially life threatening toxicities.
All together, these are promising results for the future of CAR-T therapy in solid tumors. Modifying the traditional approach of CAR-T therapy in hematologic malignancies will be necessary to achieve success in solid tumors. Tandem CAR-T development, as well as direct injection into the tumor site are both novel approaches which may aid in achieving therapeutic success in solid tumor models.
Jacqueline Carrico, MD Candidate
University of Colorado, School of Medicine
Jackie is completing her medical training in Anesthesiology and has a diverse background in basic science, translational, and clinical research.
References
Yu S, Li A, Liu Q, et al. Chimeric antigen receptor T cells: a novel therapy for solid tumors. J Hematol Oncol. 2017;10(1):78.
