Engineering CAR-T Cells for Improved Function Against Solid Tumors

Genetic engineering T cells to create clinically applied chimeric antigen receptor (CAR) T cells has led to improved patient outcomes for some forms of hematopoietic malignancies. While this has inspired the biomedical community to develop similar strategies to treat solid tumor patients, challenges such as the immunosuppressive character of the tumor microenvironment, CAR-T cell persistence and trafficking to the tumor seem to limit CAR-T cell efficacy in solid cancers. This review provides an overview of mechanisms that tumors exploit to evade eradication by CAR-T cells as well as emerging approaches that incorporate genetic engineering technologies to improve CAR-T cell activity against solid tumors.

[1]  Theresa Kaeuferle,et al.  Induction of a central memory and stem cell memory phenotype in functionally active CD4+ and CD8+ CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19+ acute lymphoblastic leukemia , 2018, Cancer Immunology, Immunotherapy.

[2]  A. Bagg,et al.  Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. , 2011, The New England journal of medicine.

[3]  S. Jagannath,et al.  Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-Bcma CAR T Cell Therapy , 2017 .

[4]  A. Lowy,et al.  The chemokine receptor CXCR4 is expressed in pancreatic intraepithelial neoplasia , 2008, Gut.

[5]  R. Ferris Immunology and Immunotherapy of Head and Neck Cancer. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  R. Katoh,et al.  Expression of CXCR4 and its ligand SDF-1 in intestinal-type gastric cancer is associated with lymph node and liver metastasis. , 2009, Anticancer research.

[7]  D. Trono,et al.  A Third-Generation Lentivirus Vector with a Conditional Packaging System , 1998, Journal of Virology.

[8]  G. Dranoff,et al.  CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer. , 2011, Cancer research.

[9]  Z. Estrov,et al.  Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway , 2018, Leukemia.

[10]  H. Abken,et al.  CAR T Cells Releasing IL-18 Convert to T-Bethigh FoxO1low Effectors that Exhibit Augmented Activity against Advanced Solid Tumors. , 2017, Cell reports.

[11]  J. Friedberg,et al.  Lymphoma Remissions Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-15 Levels. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  S. Rosenberg,et al.  Long-Duration Complete Remissions of Diffuse Large B Cell Lymphoma after Anti-CD19 Chimeric Antigen Receptor T Cell Therapy. , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[13]  Mohammad Aqdas,et al.  TLR-3 Stimulation Skews M2 Macrophages to M1 Through IFN-αβ Signaling and Restricts Tumor Progression , 2018, Front. Immunol..

[14]  Zhiyuan Hu,et al.  LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. , 2014, Cancer research.

[15]  R. Pope,et al.  IL-17 Induces Monocyte Migration in Rheumatoid Arthritis1 , 2009, The Journal of Immunology.

[16]  C. June,et al.  A Chimeric Switch-Receptor Targeting PD1 Augments the Efficacy of Second-Generation CAR T Cells in Advanced Solid Tumors. , 2016, Cancer research.

[17]  Sadik H. Kassim,et al.  Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  E. Tartour,et al.  Tim-3 Expression on Tumor-Infiltrating PD-1+CD8+ T Cells Correlates with Poor Clinical Outcome in Renal Cell Carcinoma. , 2017, Cancer research.

[19]  T. Sparwasser,et al.  Regulatory T cells in the bone marrow microenvironment in patients with prostate cancer , 2012, Oncoimmunology.

[20]  Rugang Zhang,et al.  SATB1 Expression Governs Epigenetic Repression of PD‐1 in Tumor‐Reactive T Cells , 2017, Immunity.

[21]  A. Sluder,et al.  AMD3100 Augments the Efficacy of Mesothelin-Targeted, Immune-Activating VIC-008 in Mesothelioma by Modulating Intratumoral Immunosuppression , 2018, Cancer Immunology Research.

[22]  Chiara Bonini,et al.  T memory stem cells in health and disease , 2017, Nature Medicine.

[23]  M. Sadelain,et al.  CAR T cell–induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade , 2018, Nature Medicine.

[24]  C. June,et al.  Dominant-Negative TGF-β Receptor Enhances PSMA-Targeted Human CAR T Cell Proliferation And Augments Prostate Cancer Eradication. , 2018, Molecular therapy : the journal of the American Society of Gene Therapy.

[25]  R. Ahmed,et al.  mTOR regulates memory CD8 T cell differentiation , 2009, Nature.

[26]  J. Viola,et al.  IFN-γ Production by CD8+ T Cells Depends on NFAT1 Transcription Factor and Regulates Th Differentiation1 , 2005, The Journal of Immunology.

[27]  Xiuli Wang,et al.  Ex vivo Akt inhibition promotes the generation of potent CD19CAR T cells for adoptive immunotherapy , 2015, Journal of Immunotherapy for Cancer.

[28]  A. Schambach,et al.  Context dependence of different modules for posttranscriptional enhancement of gene expression from retroviral vectors. , 2000, Molecular therapy : the journal of the American Society of Gene Therapy.

[29]  Fei Xing,et al.  Cancer associated fibroblasts (CAFs) in tumor microenvironment. , 2010, Frontiers in bioscience.

[30]  H. Abken,et al.  IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively Muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression. , 2011, Cancer research.

[31]  G. Lucignani,et al.  Nitric Oxide Generated by Tumor-Associated Macrophages Is Responsible for Cancer Resistance to Cisplatin and Correlated With Syntaxin 4 and Acid Sphingomyelinase Inhibition , 2018, Front. Immunol..

[32]  Jeng-Jong Hwang,et al.  Serial Low Doses of Sorafenib Enhance Therapeutic Efficacy of Adoptive T Cell Therapy in a Murine Model by Improving Tumor Microenvironment , 2014, PloS one.

[33]  R. Xiang,et al.  Cancer Associated Fibroblasts Promote Tumor Growth and Metastasis by Modulating the Tumor Immune Microenvironment in a 4T1 Murine Breast Cancer Model , 2009, PloS one.

[34]  Mithat Gonen,et al.  Long‐Term Follow‐up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia , 2018, The New England journal of medicine.

[35]  Pamela A Shaw,et al.  Chimeric antigen receptor T cells for sustained remissions in leukemia. , 2014, The New England journal of medicine.

[36]  Wei Zhang,et al.  CXCL12/CXCR4: a symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks , 2016, Oncogene.

[37]  E. Puré,et al.  Augmentation of CAR T-cell Trafficking and Antitumor Efficacy by Blocking Protein Kinase A Localization , 2016, Cancer Immunology Research.

[38]  Travis J Cohoon,et al.  Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. , 2013, Cancer discovery.

[39]  Chen Xinming,et al.  Expression of CXCR4 in oral squamous cell carcinoma: correlations with clinicopathology and pivotal role of proliferation. , 2010, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[40]  Antonio Lanzavecchia,et al.  Central memory and effector memory T cell subsets: function, generation, and maintenance. , 2004, Annual review of immunology.

[41]  Stephen J. Schuster,et al.  Chimeric Antigen Receptor T Cells in Refractory B‐Cell Lymphomas , 2017, The New England journal of medicine.

[42]  S. Heimfeld,et al.  Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor–modified T cells , 2016, Science Translational Medicine.

[43]  S. Riddell,et al.  The Nonsignaling Extracellular Spacer Domain of Chimeric Antigen Receptors Is Decisive for In Vivo Antitumor Activity , 2014, Cancer Immunology Research.

[44]  J. Shepherd,et al.  Cycle. , 2020, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[45]  H. Heslop,et al.  Fine-tuning the CAR spacer improves T-cell potency , 2016, Oncoimmunology.

[46]  Yu Chen,et al.  Genome editing of CXCR4 by CRISPR/cas9 confers cells resistant to HIV-1 infection , 2015, Scientific Reports.

[47]  T. Senga,et al.  Lenalidomide enhances the function of chimeric antigen receptor T cells against the epidermal growth factor receptor variant III by enhancing immune synapses , 2015, Cancer Gene Therapy.

[48]  D. Maloney,et al.  Accepted Article Preview : Published ahead of advance online publication , 2016 .

[49]  Shilpa Gupta,et al.  PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. , 2014, Cancer control : journal of the Moffitt Cancer Center.

[50]  E. Mardis,et al.  Temporally Distinct PD-L1 Expression by Tumor and Host Cells Contributes to Immune Escape , 2017, Cancer Immunology Research.

[51]  Jennifer A. Doudna,et al.  Generation of knock-in primary human T cells using Cas9 ribonucleoproteins , 2015, Proceedings of the National Academy of Sciences.

[52]  A. Scharenberg,et al.  Homology-Directed Recombination for Enhanced Engineering of Chimeric Antigen Receptor T Cells , 2017, Molecular therapy. Methods & clinical development.

[53]  R. Jain,et al.  CXCR4 inhibition in tumor microenvironment facilitates anti‐programmed death receptor‐1 immunotherapy in sorafenib‐treated hepatocellular carcinoma in mice , 2015, Hepatology.

[54]  K. Davis,et al.  Tisagenlecleucel in Children and Young Adults with B‐Cell Lymphoblastic Leukemia , 2018, The New England journal of medicine.

[55]  A. Halpern,et al.  Primary T Cells from Cutaneous T-cell Lymphoma Skin Explants Display an Exhausted Immune Checkpoint Profile , 2018, Cancer Immunology Research.

[56]  F. Marincola,et al.  Enhanced antitumor activity induced by adoptive T-cell transfer and adjunctive use of the histone deacetylase inhibitor LAQ824. , 2009, Cancer research.

[57]  Adrian J. Thrasher,et al.  Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells , 2017, Science Translational Medicine.

[58]  Syed Abbas Ali,et al.  T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. , 2016, Blood.

[59]  Brian Keith,et al.  Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation. , 2018, JCI insight.

[60]  Carl H. June,et al.  A versatile system for rapid multiplex genome-edited CAR T cell generation , 2017, Oncotarget.

[61]  L. Naldini,et al.  Exploiting microRNA regulation for genetic engineering. , 2012, Tissue antigens.

[62]  T. Blankenstein,et al.  Retroviral vectors for high-level transgene expression in T lymphocytes. , 2003, Human gene therapy.

[63]  Yan Song,et al.  Histone deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors , 2018, Leukemia.

[64]  T. Forsthuber,et al.  T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. , 2015, Cytokine.

[65]  Noam Brown,et al.  The role of tumour‐associated macrophages in tumour progression: implications for new anticancer therapies , 2002, The Journal of pathology.

[66]  T. Kohwi-Shigematsu,et al.  SATB1 targets chromatin remodelling to regulate genes over long distances , 2002, Nature.

[67]  L. Appleman,et al.  CD28 Costimulation Mediates Down-Regulation of p27kip1 and Cell Cycle Progression by Activation of the PI3K/PKB Signaling Pathway in Primary Human T Cells1 , 2002, The Journal of Immunology.

[68]  L. Arseniev,et al.  Automated Enrichment, Transduction, and Expansion of Clinical-Scale CD62L+ T Cells for Manufacturing of Gene Therapy Medicinal Products , 2016, Human gene therapy.

[69]  A. Baer,et al.  Src-family kinases negatively regulate NFAT signaling in resting human T cells , 2017, PloS one.

[70]  Bernd Hauck,et al.  Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. , 2013, The New England journal of medicine.

[71]  Douglas B. Evans,et al.  High Levels of Expression of Human Stromal Cell–Derived Factor-1 Are Associated with Worse Prognosis in Patients with Stage II Pancreatic Ductal Adenocarcinoma , 2010, Cancer Epidemiology, Biomarkers & Prevention.

[72]  Melba Marie Tejera,et al.  Signal Integration by Akt Regulates CD8 T Cell Effector and Memory Differentiation , 2012, The Journal of Immunology.

[73]  M. Moore,et al.  Simultaneous production of tumor necrosis factor-alpha and lymphotoxin by normal T cells after induction with IL-2 and anti-T3. , 1988, Journal of immunology.

[74]  W. Han,et al.  CD138-directed adoptive immunotherapy of chimeric antigen receptor (CAR)-modified T cells for multiple myeloma , 2016 .

[75]  M. Sabatino,et al.  Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. , 2016, Blood.

[76]  N. Hens,et al.  Abundant expression of TIM-3, LAG-3, PD-1 and PD-L1 as immunotherapy checkpoint targets in effusions of mesothelioma patients , 2017, Oncotarget.

[77]  Jing Zhao,et al.  Chinese a Nti鄄 Cancer a Ssociation , 2022 .

[78]  E. Kubista,et al.  MMP-2 and MMP-9 Expression in Breast Cancer-Derived Human Fibroblasts is Differentially Regulated by Stromal-Epithelial Interactions , 2002, Breast Cancer Research and Treatment.

[79]  R. Orentas,et al.  Reduction of MDSCs with All-trans Retinoic Acid Improves CAR Therapy Efficacy for Sarcomas , 2016, Cancer Immunology Research.

[80]  M. Postow,et al.  Immune checkpoint inhibitor combinations in solid tumors: opportunities and challenges. , 2016, Immunotherapy.

[81]  F. Gu,et al.  Increased expression of SDF‐1/CXCR4 is associated with lymph node metastasis of invasive micropapillary carcinoma of the breast , 2009, Histopathology.

[82]  I. Mellman,et al.  Oncology meets immunology: the cancer-immunity cycle. , 2013, Immunity.

[83]  J. Utikal,et al.  Targeting Myeloid-Derived Suppressor Cells to Bypass Tumor-Induced Immunosuppression , 2018, Front. Immunol..

[84]  Wendell A. Lim,et al.  Remote control of therapeutic T cells through a small molecule–gated chimeric receptor , 2015, Science.

[85]  A. Vater,et al.  Increasing Tumor-Infiltrating T Cells through Inhibition of CXCL12 with NOX-A12 Synergizes with PD-1 Blockade , 2017, Cancer Immunology Research.

[86]  S. Karam,et al.  Resistance to Radiotherapy and PD-L1 Blockade Is Mediated by TIM-3 Upregulation and Regulatory T-Cell Infiltration , 2018, Clinical Cancer Research.

[87]  J. Orange,et al.  Tonic 4-1BB Costimulation in Chimeric Antigen Receptors Impedes T Cell Survival and Is Vector-Dependent. , 2017, Cell reports.

[88]  G. Coukos,et al.  Distinct Effects of IL-18 on the Engraftment and Function of Human Effector CD8+ T Cells and Regulatory T Cells , 2008, PloS one.

[89]  Derek S. Chan,et al.  Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in pancreatic cancer , 2013, Proceedings of the National Academy of Sciences.

[90]  Katy Rezvani,et al.  Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. , 2016, The Journal of clinical investigation.

[91]  A. Alavi,et al.  Opportunities and Challenges , 1998, In Vitro Diagnostic Industry in China.

[92]  David A. Williams,et al.  Equal potency of gammaretroviral and lentiviral SIN vectors for expression of O6-methylguanine-DNA methyltransferase in hematopoietic cells. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[93]  Y. Nakanishi,et al.  Association of PD-L1 overexpression with activating EGFR mutations in surgically resected nonsmall-cell lung cancer. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[94]  A. Lanfranco,et al.  CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms , 2004, Molecular and Cellular Biology.

[95]  Michael L. Wang,et al.  T Cells Genetically Modified to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[96]  Tae Woo Kim,et al.  Matrix Metalloproteinase-9 in Monocytic Myeloid-Derived Suppressor Cells Correlate with Early Infections and Clinical Outcomes in Allogeneic Hematopoietic Stem Cell Transplantation. , 2018, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[97]  X. Xue,et al.  Stromal cell-derived factor-1 (SDF-1)/CXCR4 axis enhances cellular invasion in ovarian carcinoma cells via integrin β1 and β3 expressions. , 2014, Oncology research.

[98]  C. June,et al.  Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18 , 2017, Cell reports.

[99]  L. Palmer,et al.  PI3K orchestration of the in vivo persistence of chimeric antigen receptor-modified T cells , 2018, Leukemia.

[100]  J. Qian,et al.  mTOR-mediated glycolysis contributes to the enhanced suppressive function of murine tumor-infiltrating monocytic myeloid-derived suppressor cells , 2018, Cancer Immunology, Immunotherapy.

[101]  Tiberiu Popescu,et al.  Lactate – A new frontier in the immunology and therapy of prostate cancer , 2017, Journal of cancer research and therapeutics.

[102]  Dennis C. Sgroi,et al.  Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion , 2005, Cell.

[103]  S. Ryser,et al.  High affinity anti-TIM-3 and anti-KIR monoclonal antibodies cloned from healthy human individuals , 2017, PloS one.

[104]  Z. Estrov,et al.  The CXCR4–STAT3–IL-10 Pathway Controls the Immunoregulatory Function of Chronic Lymphocytic Leukemia and Is Modulated by Lenalidomide , 2018, Front. Immunol..

[105]  E. Wherry,et al.  Molecular and cellular insights into T cell exhaustion , 2015, Nature Reviews Immunology.

[106]  Hinrich Abken,et al.  TRUCKs: the fourth generation of CARs , 2015, Expert opinion on biological therapy.

[107]  E. Tartour,et al.  Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer , 2017, ESMO Open.

[108]  Yu Huang,et al.  Chemokine axes CXCL12/CXCR4 and CXCL16/CXCR6 correlate with lymph node metastasis in epithelial ovarian carcinoma , 2011, Chinese journal of cancer.

[109]  A. Peled,et al.  Interaction between neoplastic cells and cancer-associated fibroblasts through the CXCL12/CXCR4 axis: role in non-small cell lung cancer tumor proliferation. , 2011, The Journal of thoracic and cardiovascular surgery.

[110]  Y. Huang,et al.  Upregulation of PD-L1 by EGFR Activation Mediates the Immune Escape in EGFR-Driven NSCLC: Implication for Optional Immune Targeted Therapy for NSCLC Patients with EGFR Mutation , 2015, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[111]  D. Mougiakakos,et al.  Coexpressed Catalase Protects Chimeric Antigen Receptor–Redirected T Cells as well as Bystander Cells from Oxidative Stress–Induced Loss of Antitumor Activity , 2016, The Journal of Immunology.

[112]  R. Kaplan,et al.  4-1BB Costimulation Ameliorates T Cell Exhaustion Induced by Tonic Signaling of Chimeric Antigen Receptors , 2015, Nature Medicine.