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Published on: October 14, 2021
Targeting TAG-72 in cutaneous T cell lymphoma
Vera J Evtimov1,2, Maree V Hammett1,2, Aleta Pupovac1,2
1Cartherics Pty Ltd, Notting Hill, Australia.
Purpose:
Current monoclonal antibody-based treatment approaches for cutaneous T cell lymphoma (CTCL) rely heavily on the ability to identify a tumor specific target that is essentially absent on normal cells. Herein, we propose tumor associated glycoprotein-72 (TAG-72) as one such target. TAG-72 is a mucin-associated, truncated O-glycan that has been identified as a chimeric antigen receptor (CAR)-T cell target in solid tumor indications. To date, TAG-72 targeting has not been considered in the setting of hematological malignancies.
Experimental Design:
CD3+ cells from patients with CTCL were analyzed for TAG-72 expression by flow cytometry. Immunohistochemistry was used to assess TAG-72 expression in CTCL patient skin lesions and a TAG-72 ELISA was employed to assess soluble TAG-72 (CA 72-4) in patient plasma. TAG-72 CAR transduction was performed on healthy donor (HD) and CTCL T cells and characterized by flow cytometry. In vitro CAR-T cell function was assessed by flow cytometry and xCELLigence® using patient peripheral blood mononuclear cells and proof-of-concept ovarian cancer cell lines. In vivo CAR-T cell function was assessed in a proof-of-concept, TAG-72+ ovarian cancer xenograft mouse model.
Results:
TAG-72 expression was significantly higher on total CD3+ T cells and CD4+ subsets in CTCL donors across disease stages, compared to that of HDs. TAG-72 was also present in CTCL patient skin lesions, whereas CA 72-4 was detected at low levels in both CTCL patient and HD plasma with no differences between the two groups. In vitro cytotoxicity assays showed that anti-TAG-72 CAR-T cells significantly, and specifically reduced CD3+TAG-72+ expressing CTCL cells, compared to culture with unedited T cells (no CAR). CTCL CAR-T cells had comparable function to HD CAR-T cells in vitro and CAR-T cells derived from CTCL patients eradicated cancer cells in vivo.
Conclusion:
This study shows the first evidence of TAG-72 as a possible target for the treatment of CTCL.
Insights
Tumor associated glycoprotein-72 (TAG-72) is expressed on cutaneous T cell lymphoma (CTCL) cells, making it a potential target for CAR-T cell therapy. This study demonstrates TAG-72 CAR-T cells effectively target and eliminate CTCL cells both in vitro and in vivo.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Cutaneous T cell lymphoma (CTCL) treatments often require specific tumor targets absent on healthy cells.
- Tumor associated glycoprotein-72 (TAG-72), a target in solid tumors, has not been explored for hematological malignancies.
Purpose of the Study:
- To investigate TAG-72 as a potential therapeutic target for CTCL.
- To evaluate the efficacy of TAG-72-targeted chimeric antigen receptor (CAR)-T cells against CTCL.
Main Methods:
- Flow cytometry and immunohistochemistry assessed TAG-72 expression on CTCL cells and tissues.
- ELISA measured soluble TAG-72 (CA 72-4) in patient plasma.
- TAG-72 CAR-T cells were generated from healthy donors and CTCL patients for in vitro and in vivo functional assays.
Main Results:
- TAG-72 expression was significantly higher on CTCL T cells (CD3+, CD4+) compared to healthy donors.
- TAG-72 CAR-T cells specifically eradicated TAG-72+ CTCL cells in vitro.
- CAR-T cells derived from CTCL patients demonstrated in vivo efficacy in a xenograft model.
Conclusions:
- This study provides the first evidence of TAG-72 as a viable therapeutic target for CTCL.
- TAG-72 CAR-T cell therapy holds promise for treating CTCL.
