Generation of Potent T-cell Immunotherapy for Cancer Using DAP12-Based, Multichain, Chimeric Immunoreceptors

Our plain-English summary of Generation of Potent T-cell Immunotherapy for Cancer Using DAP12-Based, Multichain, Chimeric Immunoreceptors, by E. Wang, L.C. Wang, C.Y. Tsai, et al (Cancer Immunology Research, 2015).

The study

• Authors: E. Wang, L.C. Wang, C.Y. Tsai, V. Bhoj, Z. Gershenson, E. Moon, K. Newick, J. Sun, A. Lo, T. Baradet, M.D. Feldman, D. Barrett, E. Puré, S. Albelda, M.C. Milone
• Journal: Cancer Immunology Research
• Published: 2015;3(7):815-26
• Cited by: 99 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Chimeric antigen receptors (CAR) bearing an antigen-binding domain linked in cis to the cytoplasmic domains of CD3ζ and costimulatory receptors have provided a potent method for engineering T-cell cytotoxicity toward B-cell leukemia and lymphoma. However, resistance to immunotherapy due to loss of T-cell effector function remains a significant barrier, especially in solid malignancies. We describe an alternative chimeric immunoreceptor design in which we have fused a single-chain variable fragment for antigen recognition to the transmembrane and cytoplasmic domains of KIR2DS2, a stimulatory killer immunoglobulin-like receptor (KIR). We show that this simple, KIR-based CAR (KIR-CAR) triggers robust antigen-specific proliferation and effector function in vitro when introduced into human T cells with DAP12, an immunotyrosine-based activation motifs-containing adaptor. T cells modified to express a KIR-CAR and DAP12 exhibit superior antitumor activity compared with standard first- and second-generation CD3ζ-based CARs in a xenograft model of mesothelioma highly resistant to immunotherapy. The enhanced antitumor activity is associated with improved retention of chimeric immunoreceptor expression and improved effector function of isolated tumor-infiltrating lymphocytes. These results support the exploration of KIR-CARs for adoptive T-cell immunotherapy, particularly in immunotherapy-resistant solid tumors.

©2015 American Association for Cancer Research.

In plain English

This was a laboratory (preclinical) study of a chimeric immunoreceptor design in which an antigen-binding single-chain fragment was joined to the transmembrane and cytoplasmic portions of the stimulatory killer immunoglobulin-like receptor KIR2DS2 and delivered to T cells together with the adaptor DAP12 (constructs labelled SS1-KIRS2/Dap12, CD19KIRS2/Dap12 and FAP-KIRS2/Dap12). The authors compared these cells with mock-transduced T cells and with CD3-zeta-based CARs carrying no, CD28 or 4-1BB co-stimulatory domains (SS1-z, SS1-28z, SS1-BBz). Readable section headings and figure labels show that the work covered construction of the receptor and DAP12-dependent killing, cytokine release (IFN-gamma, IL-2) and proliferation against antigen-positive versus antigen-negative target cells, tumour-volume experiments in mice, and analysis of tumour-infiltrating lymphocytes with receptor expression by Western blot. The authors reported that KIR-CAR/Dap12 T cells gave potent antitumour activity in vivo and that this was associated with better maintenance of CAR expression in tumour-infiltrating lymphocytes. In the FAP-targeted experiments, panels comparing mock, DAP12-only and FAP-KIRS2/Dap12 groups reported p values below 0.0001 for the percentages of CD45-CD90+FAP+ and CD45+FAP+ cells among total live cells and p=0.03 and p=0.002 for hematocrit, while a cell-density panel (cells per mm2) comparing SS1-BBz, SS1-28z and SS1-KIRS2/DAP12 T cells was marked "ns" and "p < 0.05".

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: preclinical laboratory study: human T cells engineered in vitro plus mouse tumour xenograft experiments
• Who was studied: Engineered T cells tested against target cell lines in vitro and in tumour-bearing mice; numbers, donors and mouse strain are not legible in the supplied text
• Exposure: A KIR-based chimeric immunoreceptor (scFv fused to KIR2DS2 transmembrane and cytoplasmic domains) co-expressed with DAP12, compared with CD3-zeta-based CARs (SS1-z, SS1-28z, SS1-BBz) and mock-transduced cells
• Main results:
  • The authors reported that the KIR-CAR with DAP12 conferred cytotoxic activity that depended on DAP12
  • The authors reported that the KIR-CAR/Dap12 triggered cytokine production (IFN-gamma, IL-2 were measured) and proliferation without added co-stimulation
  • In the mouse tumour experiments the authors reported potent antitumour activity for the KIR-CAR/Dap12 T cells
  • In the FAP experiments, panels comparing mock, DAP12-only and FAP-KIRS2/Dap12 groups reported p=0.03 and p=0.002 for hematocrit
  • In the same experiment, the percentages of CD45-CD90+FAP+ and CD45+FAP+ cells among total live cells were compared across mock, DAP12-only and FAP-KIRS2/Dap12 groups with p values below 0.0001
  • A cell-density panel (cells per mm2), not a tumour-cell count, compared SS1-BBz, SS1-28z and SS1-KIRS2/DAP12 T-cell groups and was labelled 'ns' and 'p < 0.05'
  • The authors linked the greater in vivo activity to retention of receptor expression in tumour-infiltrating lymphocytes
• The authors' conclusion: The authors concluded that T cells bearing a KIR-based CAR with DAP12 showed potent antitumour activity in vivo, associated with better maintenance of receptor expression in tumour-infiltrating lymphocytes

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Immunotherapy, Mesothelioma, Tumor-Infiltrating Lymphocytes.

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