Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo

Jackson, H.J., Rafiq, S. & Brentjens, R.J. Driving CAR T-cells forward. Nat. Rev. Clin. Oncol. 13, 370–383 (2016).

Zhang, M. et al. A high M1/M2 ratio of tumor-associated macrophages is associated with extended survival in ovarian cancer patients. J. Ovarian Res. 7, 19 (2014).

Knutson, K.L. et al. Regulatory T cells, inherited variation, and clinical outcome in epithelial ovarian cancer. Cancer Immunol. Immunother. 64, 1495–1504 (2015).

Erfani, N. et al. FoxP3+ regulatory T cells in peripheral blood of patients with epithelial ovarian cancer. Iran. J. Immunol. 11, 105–112 (2014).

Shevach, E.M. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 30, 636–645 (2009).

Noy, R. & Pollard, J.W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).

Abiko, K. et al. IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. Br. J. Cancer 112, 1501–1509 (2015).

Yeku, O.O., Purdon, T.J., Koneru, M., Spriggs, D. & Brentjens, R.J. Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment. Sci. Rep. 7, 10541 (2017).

Frey, A.B. Suppression of T cell responses in the tumor microenvironment. Vaccine 33, 7393–7400 (2015).

Kershaw, M.H. et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin. Cancer Res. 12, 6106–6115 (2006).

Brahmer, J.R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562 (2014).

Topalian, S.L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

Armand, P. Immune checkpoint blockade in hematologic malignancies. Blood 125, 3393–3400 (2015).

Rizvi, N.A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).

Tumeh, P.C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

Cha, E. et al. Improved survival with T cell clonotype stability after anti-CTLA-4 treatment in cancer patients. Sci. Transl. Med. 6, 238ra70 (2014).

Gajewski, T.F., Louahed, J. & Brichard, V.G. Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J. 16, 399–403 (2010).

Ku, G.Y. et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer 116, 1767–1775 (2010).

Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).

Curran, K.J. et al. Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression. Mol. Ther. 23, 769–778 (2015).

Pegram, H.J. et al. Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood 119, 4133–4141 (2012).

Koneru, M., Purdon, T.J., Spriggs, D., Koneru, S. & Brentjens, R.J. IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. OncoImmunology 4, e994446 (2015).

Pegram, H.J. et al. IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia. Leukemia 29, 415–422 (2015).

Rafiq, S. et al. Optimized T-cell receptor-mimic chimeric antigen receptor T cells directed toward the intracellular Wilms Tumor 1 antigen. Leukemia 31, 1788–1797 (2017).

Avanzi, M.P. et al. Engineered tumor-targeted t cells mediate enhanced anti-tumor efficacy both directly and through activation of the endogenous immune system. Cell Reports 23, 2130–2141 (2018).

John, L.B. et al. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin. Cancer Res. 19, 5636–5646 (2013).

Rosewell Shaw, A. et al. Adenovirotherapy delivering cytokine and checkpoint inhibitor augments CAR T cells against metastatic head and neck cancer. Mol. Ther. 25, 2440–2451 (2017).

Chekmasova, A.A. et al. Successful eradication of established peritoneal ovarian tumors in SCID-Beige mice following adoptive transfer of T cells genetically targeted to the MUC16 antigen. Clin. Cancer Res. 16, 3594–3606 (2010).

Curran, M.A., Montalvo, W., Yagita, H. & Allison, J.P. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc. Natl. Acad. Sci. USA 107, 4275–4280 (2010).

Santos, E.B. et al. Sensitive in vivo imaging of T cells using a membrane-bound Gaussia princeps luciferase. Nat. Med. 15, 338–344 (2009).

Suarez, E.R. et al. Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model. Oncotarget 7, 34341–34355 (2016).

Prosser, M.E., Brown, C.E., Shami, A.F., Forman, S.J. & Jensen, M.C. Tumor PD-L1 co-stimulates primary human CD8+ cytotoxic T cells modified to express a PD1:CD28 chimeric receptor. Mol. Immunol. 51, 263–272 (2012).

Liu, X. et al. A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T cells in advanced solid tumors. Cancer Res. 76, 1578–1590 (2016).

Cherkassky, L. et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J. Clin. Invest. 126, 3130–3144 (2016).

Michot, J.M. et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur. J. Cancer 54, 139–148 (2016).

Grosso, J.F. et al. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J. Clin. Invest. 117, 3383–3392 (2007).

Workman, C.J. et al. Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J. Immunol. 172, 5450–5455 (2004).

Sabatos, C.A. et al. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat. Immunol. 4, 1102–1110 (2003).

Hodi, F.S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

Peterson, A.C., Russell, J.D., Bailey, D.J., Westphall, M.S. & Coon, J.J. Parallel reaction monitoring for high resolution and high mass accuracy quantitative, targeted proteomics. Mol. Cell. Proteomics 11, 1475–1488 (2012).

Egertson, J.D., MacLean, B., Johnson, R., Xuan, Y. & MacCoss, M.J. Multiplexed peptide analysis using data-independent acquisition and Skyline. Nat. Protoc. 10, 887–903 (2015).

Shevchenko, A., Tomas, H., Havlis, J., Olsen, J.V. & Mann, M. In-gel digestion for mass spectrometric characterization of proteins and proteomes. Nat. Protoc. 1, 2856–2860 (2006).

Rappsilber, J., Mann, M. & Ishihama, Y. Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat. Protoc. 2, 1896–1906 (2007).

Lee, A.Y. et al. Measurement of fractional synthetic rates of multiple protein analytes by triple quadrupole mass spectrometry. Clin. Chem. 58, 619–627 (2012).