T cell-targeting nanoparticles focus delivery of immunotherapy to improve antitumor immunity

Targeted delivery of compounds to particular cell subsets can enhance therapeutic index by concentrating their action on the cells of interest. Because attempts to target tumors directly have yielded limited benefit, we instead target endogenous immune cell subsets in the circulation that can migrate actively into tumors. We describe antibody-targeted nanoparticles that bind to CD8+ T cells in the blood, lymphoid tissues, and tumors of mice. PD-1+ T cells are successfully targeted in the circulation and tumor. The delivery of an inhibitor of TGFβ signaling to PD-1-expressing cells extends the survival of tumor-bearing mice, whereas free drugs have no effect at such doses. This modular platform also enables PD-1-targeted delivery of a TLR7/8 agonist to the tumor microenvironment, increasing the proportion of tumor-infiltrating CD8+ T cells and sensitizing tumors to subsequent anti-PD-1. Targeted delivery of immunotherapy to defined subsets of endogenous leukocytes may be superior to administration of free drugs.Targeted delivery of immunomodulatory compounds to defined subsets of endogenous immune cells may improve the efficacy of combination immunotherapies. Here, the authors use PD-1-targeting nanoparticles containing a TGFβ inhibitor or a TLR7/8 agonist to deliver these payloads to T cells or via T cells to the tumor microenvironment, respectively, leading to anti-tumor efficacy in vivo.

[1]  J. Taube,et al.  Durable Cancer Regression Off-Treatment and Effective Reinduction Therapy with an Anti-PD-1 Antibody , 2012, Clinical Cancer Research.

[2]  E. Faghihloo,et al.  Evaluation of antitumor activity of a TGF-beta receptor I inhibitor (SD-208) on human colon adenocarcinoma , 2014, DARU Journal of Pharmaceutical Sciences.

[3]  J. Gartner,et al.  Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients , 2016, Nature Medicine.

[4]  D. Irvine,et al.  Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles. , 2012, Biomaterials.

[5]  P. Bragado,et al.  TGFβ2 dictates disseminated tumour cell fate in target organs through TGFβ-RIII and p38α/β signalling , 2013, Nature Cell Biology.

[6]  Sukgil Song,et al.  Resiquimod, a TLR7/8 agonist, promotes differentiation of myeloid-derived suppressor cells into macrophages and dendritic cells , 2014, Archives of pharmacal research.

[7]  C. Drake,et al.  Stereotactic Radiation Therapy Augments Antigen-Specific PD-1–Mediated Antitumor Immune Responses via Cross-Presentation of Tumor Antigen , 2014, Cancer Immunology Research.

[8]  Hua Tang,et al.  SD-208, a Novel Protein Kinase D Inhibitor, Blocks Prostate Cancer Cell Proliferation and Tumor Growth In Vivo by Inducing G2/M Cell Cycle Arrest , 2015, PloS one.

[9]  C. Rudin,et al.  Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  Russell J Mumper,et al.  Biotargeted nanomedicines for cancer: six tenets before you begin. , 2013, Nanomedicine.

[11]  J. Lunceford,et al.  Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. , 2016, The Lancet. Oncology.

[12]  M. Mahmoudi,et al.  Impact of protein pre-coating on the protein corona composition and nanoparticle cellular uptake. , 2016, Biomaterials.

[13]  M. Postow,et al.  Treatment of the Immune-Related Adverse Effects of Immune Checkpoint Inhibitors: A Review. , 2016, JAMA oncology.

[14]  J. Yingling,et al.  Development of TGF-beta signalling inhibitors for cancer therapy. , 2004, Nature reviews. Drug discovery.

[15]  Robert Langer,et al.  Preclinical Development and Clinical Translation of a PSMA-Targeted Docetaxel Nanoparticle with a Differentiated Pharmacological Profile , 2012, Science Translational Medicine.

[16]  J. Wolchok,et al.  GITR Pathway Activation Abrogates Tumor Immune Suppression through Loss of Regulatory T-cell Lineage Stability , 2013, Cancer Immunology Research.

[17]  Prakrit V. Jena,et al.  P-selectin is a nanotherapeutic delivery target in the tumor microenvironment , 2016, Science Translational Medicine.

[18]  T. Gajewski The Next Hurdle in Cancer Immunotherapy: Overcoming the Non-T-Cell-Inflamed Tumor Microenvironment. , 2015, Seminars in oncology.

[19]  Jason Park,et al.  Paracrine co-delivery of TGF-β and IL-2 using CD4-targeted nanoparticles for induction and maintenance of regulatory T cells. , 2015, Biomaterials.

[20]  C. Ahonen,et al.  Dendritic cell maturation and subsequent enhanced T-cell stimulation induced with the novel synthetic immune response modifier R-848. , 1999, Cellular immunology.

[21]  D. Douek,et al.  PD-1 identifies the patient-specific CD8⁺ tumor-reactive repertoire infiltrating human tumors. , 2014, The Journal of clinical investigation.

[22]  M. Weller,et al.  SD-208, a Novel Transforming Growth Factor β Receptor I Kinase Inhibitor, Inhibits Growth and Invasiveness and Enhances Immunogenicity of Murine and Human Glioma Cells In vitro and In vivo , 2004, Cancer Research.

[23]  M. Hersberger,et al.  Deliberate removal of T cell help improves virus-neutralizing antibody production , 2004, Nature Immunology.

[24]  P. A. Futreal,et al.  Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. , 2012, The New England journal of medicine.

[25]  J. Geddes,et al.  What is a randomised controlled trial? , 2009, Epidemiologia e Psichiatria Sociale.

[26]  P. Jung,et al.  Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. , 2012, Cancer cell.

[27]  Soong Ho Um,et al.  Therapeutic cell engineering using surface-conjugated synthetic nanoparticles , 2010, Nature Medicine.

[28]  Y. Shentu,et al.  Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial , 2016, The Lancet.

[29]  Jason Park,et al.  Modulation of CD4+ T lymphocyte lineage outcomes with targeted, nanoparticle-mediated cytokine delivery. , 2011, Molecular pharmaceutics.

[30]  Julian Tang Rejuvenation , 1928, Nature.

[31]  Miles A. Miller,et al.  In vivo imaging reveals a tumor-associated macrophage–mediated resistance pathway in anti–PD-1 therapy , 2017, Science Translational Medicine.

[32]  D. Irvine,et al.  Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells , 2015, Science Translational Medicine.

[33]  Hamidreza Ghandehari,et al.  Nanoparticle Uptake: The Phagocyte Problem. , 2015, Nano today.

[34]  Darrell J Irvine,et al.  In vivo targeting of adoptively transferred T-cells with antibody- and cytokine-conjugated liposomes. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[35]  Jonathan M. Yingling,et al.  Development of TGF-β signalling inhibitors for cancer therapy , 2004, Nature Reviews Drug Discovery.

[36]  I. Mellman,et al.  Elements of cancer immunity and the cancer–immune set point , 2017, Nature.

[37]  J. Shimizu,et al.  Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance , 2002, Nature Immunology.

[38]  David S. Jones,et al.  Efficient drug delivery and induction of apoptosis in colorectal tumors using a death receptor 5-targeted nanomedicine. , 2014, Molecular therapy : the journal of the American Society of Gene Therapy.

[39]  R. Jain,et al.  Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. , 2013, Cancer research.

[40]  Joshua J. Breunig,et al.  T-cell TGF-β signaling abrogation restricts medulloblastoma progression , 2014, Proceedings of the National Academy of Sciences.

[41]  S. Barry,et al.  Aurora kinase inhibitor nanoparticles target tumors with favorable therapeutic index in vivo , 2016, Science Translational Medicine.

[42]  T. Graeber,et al.  Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells , 2016, Cancer Immunology Research.

[43]  R. Koup,et al.  Toll-Like Receptor Ligands Modulate Dendritic Cells to Augment Cytomegalovirus- and HIV-1-Specific T Cell Responses 1 , 2003, The Journal of Immunology.

[44]  Wolfgang A. Weber,et al.  Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging , 2007, Proceedings of the National Academy of Sciences.

[45]  Paul G. Thomas,et al.  De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation , 2017, Cell.

[46]  H. Moses,et al.  The roles of TGFβ in the tumour microenvironment , 2013, Nature Reviews Cancer.

[47]  J. Wolchok,et al.  Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. , 2016, JAMA.

[48]  H. Cantor,et al.  Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity , 2016, Proceedings of the National Academy of Sciences.

[49]  Robert C. Wolpert,et al.  A Review of the , 1985 .

[50]  George Coukos,et al.  Cancer immunotherapy comes of age , 2011, Nature.