Research

Innate immunity and signaling mechanisms

One reason many current forms of cancer immunotherapy have low clinical response rates is because they fail to activate the innate immune system - a prerequisite for forming long-lasting adaptive immune responses that are necessary to eliminate tumors and prevent their recurrence.  

Several CCIR members are investigating the development and function of innate immune cells and receptor-mediated signal transduction pathways leading to expression of cytokines and costimulatory molecules involved in T cell activation and differentiation in order to find ways to enable cancer immunotherapy to activate innate immunity leading to durable anti-tumor T cell responses.  

Some highlights from Fiscal Year 2013 include:  

• A recent study used unbiased approaches to demonstrate that vimentin is a shared autoantigen recognized by nonstereotyped follicular lymphoma BCRs and also recognized by the Igs of mantle cell lymphoma and multiple myeloma, suggesting that vimentin may play a role in the pathogenesis of multiple B cell malignancies (Cha SC, J Immunol. 2013)
• Findings from a study published in Nature established OTUD7B, a novel deubiquitinase, as a crucial regulator of signal-induced non-canonical NF-κB activation, allowing the authors to propose a mechanism of immune regulation that involves OTUD7B-mediated deubiquitination and stabilization of TRAF3 (Hu H, Nature, 2013)
• CD13+ bone marrow-derived myeloid cells promote angiogenesis, tumor growth, and metastasis (Dondossola E, PNAS. 2013)

Additional Relevant Publications

• Chodaczek G, Papanna V, Zal MA, Zal T. Body-barrier surveillance by epidermal γδ TCRs. Nat Immunol. 2012, 13(3):272-82.
• Li HS, Gelbard A, Martinez GJ, Esashi E, Zhang H, Nguyen-Jackson H, Liu YJ, Overwijk WW, Watowich SS. Cell-intrinsic role for IFN-α-STAT1 signals in regulating murine Peyer patch plasmacytoid dendritic cells and conditioning an inflammatory response. Blood. 2011, 118(14):3879-89.
• Zhang Z, Yuan B, Bao M, Lu N, Kim T, Liu YJ. The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat Immunol. 2011, 12(10):959-65.
• Zhang Z, Kim T, Bao M, Facchinetti V, Jung SY, Ghaffari AA, Qin J, Cheng G, Liu YJ. DDX1, DDX21, and DHX36 helicases form a complex with the adaptor molecule TRIF to sense dsRNA in dendritic cells. Immunity. 2011, 34(6):866-78.
• Kim T, Pazhoor S, Bao M, Zhang Z, Hanabuchi S, Facchinetti V, Bover L, Plumas J, Chaperot L, Qin J, Liu YJ. Aspartate-glutamate-alanine- histidine box motif (DEAH)/RNA helicase A helicases sense microbial DNA in human plasmacytoid dendritic cells. Proc Natl Acad Sci U S A. 2010, 107(34):15181-6.
• Castillo EF, Acero LF, Stonier SW, Zhou D, Schluns KS. Thymic and peripheral microenvironments differentially mediate development and maturation of iNKT cells by IL-15 transpresentation. Blood. 2010, 116(14):2494-503.
• Zhang H, Nguyen-Jackson H, Panopoulos AD, Li HS, Murray PJ, Watowich SS.STAT3 controls myeloid progenitor growth during emergency granulopoiesis. Blood. 2010, 116(14):2462-71.
• Li H, Hong S, Qian J, Zheng Y, Yang J, Yi Q. Cross talk between the bone and immune systems: osteoclasts function as antigen-presenting cells and activate CD4+ and CD8+ T cells. Blood. 2010, 116(2):210-7.
• Nguyen-Jackson H, Panopoulos AD, Zhang H, Li HS, Watowich SS. STAT3 controls the neutrophil migratory response to CXCR2 ligands by direct activation of G-CSF-induced CXCR2 expression and via modulation of CXCR2 signal transduction.  Blood. 2010, 115(16):3354-63.
• Arima K, Watanabe N, Hanabuchi S, Chang M, Sun SC, Liu YJ. Distinct signal codes generate dendritic cell functional plasticity. Sci Signal. 2010, Jan 19;3(105):ra4.
• Fontenot D, He H, Hanabuchi S, Nehete PN, Zhang M, Chang M, Nehete B, Wang YH, Wang YH, Ma ZM, Lee HC, Ziegler SF, Courtney AN, Miller CJ, Sun SC, Liu YJ, Sastry KJ. TSLP production by epithelial cells exposed to immunodeficiency virus triggers DC-mediated mucosal infection of CD4+ T cells. Proc Natl Acad Sci U S A. 2009, 106(39):16776-81.
• Chang M, Jin W, Sun SC. Peli1 facilitates TRIF-dependent Toll-like receptor signaling and proinflammatory cytokine production. Nat Immunol 2009, 10(10):1089-95.
• Castillo EF, Stonier SW, Frasca L, Schluns KS. Dendritic cells support the in vivo development and maintenance of NK cells via IL-15 trans-presentation.  J Immunol. 2009, 183(8):4948-56.
• Cao W, Bover L, Cho M, Hanabuchi S, Bao M, Rosen DB, Wang Y-H,Shaw JL, Du Q, Arai N, Yao Z, Lanier LL, Liu Y-J. Regulation of TLR7/9 Responses in Plasmacytoid Dendritic Cells by BST2 and ILT7 Receptor Interaction. J Exp Med 2009, 206(7):1603-14.
• Ganguly D, Chamilos G, Lande R, Gregorio J, Meller S, Facchinetti V, Homey B, Barrat FJ, Zal T, Gilliet M. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J Exp Med 2009, 206(9): 1983-94.
• Lu N, Wang YH, Wang YH, Arima K, Hanabuchi S, Liu YJ. TSLP and IL-7 use two different mechanisms to regulate human CD4+ T cell homeostasis. J Exp Med 2009, 206(10): 2111-9.
• Esashi E, Wang YH, Perng O, Qin XF, Liu YJ, Watowich SS. The signal transducer STAT5 inhibits plasmacytoid dendritic cell development by suppressing transcription factor IRF8. Immunity. 2008, 28(4):509-20.
• Zhang M, Wu X, Lee AJ, Jin W, Chang M, Wright A, Imaizumi T, Sun SC.Regulation of IkappaB kinase-related kinases and antiviral responses by tumor suppressor CYLD.  J Biol Chem. 2008, 283(27):18621-6.

Immune tolerance and T-cell function

Overview:  CD4+ helper T cells mediate cellular immunity and tissue inflammation as well as help the activation of B cells and CD8+ T cells. CD8+ cytotoxic T cells (CTLs) function as important anti-tumor effector cells in addition to mediating anti-viral immunity. Immunosuppressive regulatory T (Treg) cells function to maintain normal immune homeostasis and prevent autoimmunity; however, this population of T cells also hampers anti-tumor immunity. Thus, several CCIR members continue to study the development, function and homeostasis of different T cell subsets in order to find ways to manipulate the adaptive immune system for improving the efficacy of cancer immunotherapy.

Some highlights from the past year include:  
• 4-1BB agonist antibody treatment induces a population of KLRG1+ T cells that infiltrate melanoma tumors and investigation of the origin and function of these cells, as well as their place within established T cell paradigms revealed that these T cells, particularly the CD4 lineage, represent a novel phenotype characterized by enhanced, multipotent cytotoxicity; this novel phenotype resolves multiple questions associated with 4-1BB activation, including how 4-1BB enhances tumor-specific cytotoxicity and how 4-1BB can promote tumor immunity while repressing autoimmunity (Curran MA, J Exp Med. 2013)

Additional Relevant Publications:

• Liu X, Yan X, Zhong B, Nurieva RI, Wang A, Wang X, Martin-Orozco N, Wang Y, Chang SH, Esplugues E, Flavell RA, Tian Q, Dong C. Bcl6 expression specifies the T follicular helper cell program in vivo. J Exp Med. 2012, 209(10):1841-52. 
• Reynolds JM, Martinez GJ, Chung Y, Dong C. Toll-like receptor 4 signaling in T cells promotes autoimmune inflammation. Proc Natl Acad Sci U S A. 2012, 109(32):13064-9. 
• Chang JH, Xiao Y, Hu H, Jin J, Yu J, Zhou X, Wu X, Johnson HM, Akira S, Pasparakis M, Cheng X, Sun SC. Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells. Nat  Immunol. 2012, 13(5):481-90.
• Nurieva RI, Podd A, Chen Y, Alekseev AM, Yu M, Qi X, Huang H, Wen R, Wang J, Li HS, Watowich SS, Qi H, Dong C, Wang D. STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. J Biol Chem. 2012, 287(14):11234-9. 
• Wang X, Zhang Y, Yang XO, Nurieva RI, Chang SH, Ojeda SS, Kang HS, Schluns KS, Gui J, Jetten AM, Dong C. Transcription of Il17 and Il17f is controlled by conserved noncoding sequence 2. Immunity. 2012, 36(1):23-31. 
• Chang M, Jin W, Chang JH, Xiao Y, Brittain GC, Yu J, Zhou X, Wang YH, Cheng X, Li P, Rabinovich BA, Hwu P, Sun SC. The ubiquitin ligase Peli1 negatively regulates T cell activation and prevents autoimmunity. Nat Immunol. 2011, 12(10):1002-9. 
• Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S, Wang YH, Lim H, Reynolds JM, Zhou XH, Fan HM, Liu ZM, Neelapu SS, Dong C. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med. 2011, 17(8):983-8. 
• Hu H, Wu X, Jin W, Chang M, Cheng X, Sun SC. Noncanonical NF-kappaB regulates  inducible costimulator (ICOS) ligand expression and T follicular helper cell development. Proc Natl Acad Sci U S A. 2011, 108(31):12827-32. 
• Yamazaki T, Goya I, Graf D, Craig S, Martin-Orozco N, Dong C. A butyrophilin family member critically inhibits T cell activation. J Immunol. 2010, 185(10):5907-14. 
• Carreño R, Brown WS, Li D, Hernandez JA, Wang Y, Kim TK, Craft JW Jr, Komanduri KV, Radvanyi LG, Hwu P, Molldrem JJ, Legge GB, McIntyre BW, Ma Q. 2E8 binds to the high affinity I-domain in a metal ion-dependent manner: a second generation monoclonal antibody selectively targeting activated LFA-1. J Biol Chem. 2010, 285(43):32860-8. 
• Martinez GJ, Zhang Z, Reynolds JM, Tanaka S, Chung Y, Liu T, Robertson E, Lin X, Feng XH, Dong C. Smad2 positively regulates the generation of Th17 cells. J Biol Chem. 2010, 285(38):29039-43. 
• Nurieva RI, Zheng S, Jin W, Chung Y, Zhang Y, Martinez GJ, Reynolds JM, Wang SL, Lin X, Sun SC, Lozano G, Dong C. The E3 ubiquitin ligase GRAIL regulates T cell tolerance and regulatory T cell function by mediating T cell receptor-CD3 degradation. Immunity. 2010, 32(5):670-80. 
• Reynolds JM, Pappu BP, Peng J, Martinez GJ, Zhang Y, Chung Y, Ma L, Yang XO, Nurieva RI, Tian Q, Dong C. Toll-like receptor 2 signaling in CD4(+) T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease. Immunity. 2010, 32(5):692-702. 
• Lee AJ, Wu X, Cheng H, Zhou X, Cheng X, Sun SC. CARMA1 regulation of regulatory T cell development involves modulation of interleukin-2 receptor signaling. J Biol Chem. 2010, 285(21):15696-703. 
• Angkasekwinai P, Chang SH, Thapa M, Watarai H, Dong C. Regulation of IL-9 expression by IL-25 signaling. Nat Immunol. 2010, 11(3):250-6. 
• Martinez GJ, Zhang Z, Chung Y, Reynolds JM, Lin X, Jetten AM, Feng XH, Dong C. Smad3 differentially regulates the induction of regulatory and inflammatory T cell differentiation. J Biol Chem. 2009, 284(51):35283-6. 
• Yang XO, Angkasekwinai P, Zhu J, Peng J, Liu Z, Nurieva R, Liu X, Chung Y, Chang SH, Sun B, Dong C. Requirement for the basic helix-loop-helix transcription factor Dec2 in initial TH2 lineage commitment. Nat Immunol. 2009, 10(12):1260-6. 
• Zhang Y, Reynolds JM, Chang SH, Martin-Orozco N, Chung Y, Nurieva RI, Dong C. MKP-1 is necessary for T cell activation and function. J Biol Chem. 2009, 284(45):30815-24. 
• Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, Wang YH, Dong C. Bcl6 mediates the development of T follicular helper cells. Science. 2009, 325(5943):1001-5. 
• Li D, Molldrem JJ, Ma Q. LFA-1 regulates CD8+ T cell activation via T cell receptor-mediated and LFA-1-mediated Erk1/2 signal pathways. J Biol Chem. 2009, 284(31):21001-10. 
• Jin W, Zhou XF, Yu J, Cheng X, Sun SC. Regulation of Th17 cell differentiation and EAE induction by MAP3K NIK. Blood. 2009, 113(26):6603-10. 
• Chung Y, Chang SH, Martinez GJ, Yang XO, Nurieva R, Kang HS, Ma L, Watowich SS, Jetten AM, Tian Q, Dong C. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity. 2009, 30(4):576-87.
• Liu X, Alexiou M, Martin-Orozco N, Chung Y, Nurieva RI, Ma L, Tian Q, Kollias G, Lu S, Graf D, Dong C. Cutting edge: A critical role of B and T lymphocyte attenuator in peripheral T cell tolerance induction. J Immunol. 2009, 182(8):4516-20. 
• Wang Y, Li D, Nurieva R, Yang J, Sen M, Carreño R, Lu S, McIntyre BW, Molldrem JJ, Legge GB, Ma Q. LFA-1 affinity regulation is necessary for the activation and proliferation of naive T cells. J Biol Chem. 2009, 284(19):12645-53. 
• Chang M, Lee AJ, Fitzpatrick L, Zhang M, Sun SC. NF-kappa B1 p105 regulates T cell homeostasis and prevents chronic inflammation. J Immunol. 2009, 182(5):3131-8. 
• Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, Ma L, Wang YH, Watowich SS, Jetten AM, Tian Q, Dong C. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity. 2008, 29(1):138-49. 
• Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, Pappu BP, Shah B, Chang SH, Schluns KS, Watowich SS, Feng XH, Jetten AM, Dong C. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity. 2008, 29(1):44-56. 
• Pappu BP, Borodovsky A, Zheng TS, Yang X, Wu P, Dong X, Weng S, Browning B, Scott ML, Ma L, Su L, Tian Q, Schneider P, Flavell RA, Dong C, Burkly LC. TL1A-DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease. J Exp Med. 2008, 205(5):1049-62. 
• Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, Ma L, Shah B, Panopoulos AD, Schluns KS, Watowich SS, Tian Q, Jetten AM, Dong C. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity. 2008, 28(1):29-39.

Inflammation and the tumor immune microenvironment

Overview:  Since chronic inflammation is associated with the formation of several types of cancer, several CCIR members study the physiological/pathological roles of NF-kB signaling pathways, Th17 cells and the IL-17 family of pro-inflammatory cytokines (IL-17A – IL-17F) in preventing/forming cancer and autoimmune disease.  Theme 3 also aims to understand how the tumor immune microenvironment can dictate the fate (i.e., survival and growth) of cancer cells.  An influx of mast cells or dendritic cells in tumors can be either a good or poor prognostic indicator, depending on the type of cancer. Several CCIR members are investigating the influence of the local tumor stroma on mast cell function in terms of promoting or suppressing tumor cell growth and survival.  And finally, CCIR members are investigating mechanisms by which tumor cells induce T-cell tolerance or responses.  Results of these studies will be translated to find ways enabling immunotherapy to restore or boost anti-tumor immunity in cancer patients.

Some highlights from Fiscal Year 2013 include:  
• Immune responses in serial tumor biopsies of patients with metastatic melanoma treated with BRAF-targeted therapy showed that treatment with BRAF inhibition enhances melanoma antigen expression and facilitates T-cell cytotoxicity and a more favorable tumor microenvironment, providing support for potential synergy of BRAF-targeted therapy and immunotherapy (Frederick D, Clin Cancer Res. 2013)
• IL-17F plays a protective role in colon cancer development, possibly via inhibiting tumor angiogenesis (Tong Z, PLoS One 2012)
• Increased levels of proteinase-3 (P3) and NE in myeloid leukemia may favor tolerance because it can lead to cross-presentation of PR1 (a peptide derived from P3 or NE) without activation of the antigen-presenting cell (Alatrash G, J Immunother. 2012)
• The BRAF (V600E) mutation in melanoma cells induces expression of IL-1a and IL-1b, which in turn, upregulates expression of PD-L1, PD-L2 and COX2 in melanoma-associated fibroblasts, endowing them with the ability to suppress anti-tumor CTL activity (Khalili JS, Clin Cancer Res. 2012)
• PR1 cross-presentation on nonhematopoietic tumors such as triple negative breast cancer reveals a novel mechanism linking innate immune cells that are the source of PR1-containing proteases, which are taken up by cancer cells, and anti-tumor adaptive immunity (Mittendorf, Cancer Res. 2012)
• Mesenchymal cells derived from the bone marrow microenvironment enhance engraftment of cord blood-derived stem cells after ex vivo co-culture (de Lima M, N Engl J Med. 2012)

Additional Relevant Publications:

• Khalili JS, Liu S, Rodriguez-Cruz TG, Whittington M, Wardell S, Liu C, Zhang M, Cooper ZA, Frederick DT, Li Y, Zhang M, Joseph RW, Bernatchez C, Ekmekcioglu S, Grimm E, Radvanyi LG, Davis RE, Davies MA, Wargo JA, Hwu P, Lizee G. Oncogenic BRAF(V600E) Promotes Stromal Cell-Mediated Immunosuppression Via Induction of Interleukin-1 in Melanoma. Clin Cancer Res. 2012,18(19):5329-40.  
• Wu RC, Liu S, Chacon JA, Wu S, Li Y, Sukhumalchandra P, Murray JL, Molldrem JJ, Hwu P, Pircher H, Lizee G, Radvanyi LG. Detection and characterization of a novel subset of CD8+CD57+ T cells in metastatic melanoma with an incompletely differentiated phenotype. Clin Cancer Res. 2012,18(9):2465-77. 
• Chang SH, Reynolds JM, Pappu BP, Chen G, Martinez GJ, Dong C. Interleukin-17C promotes Th17 cell responses and autoimmune disease via interleukin-17 receptor E. Immunity. 2011, 35(4):611-21. PubMed PMID: 21982598.
• Chang DZ, Ma Y, Ji B, Wang H, Deng D, Liu Y, Abbruzzese JL, Liu YJ, Logsdon CD, Hwu P. Mast cells in tumor microenvironment promotes the in vivo growth of pancreatic ductal adenocarcinoma. Clin Cancer Res. 2011,17(22):7015-23. PubMed PMID: 21976550.
• Xu T, Wang X, Zhong B, Nurieva RI, Ding S, Dong C. Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORgamma t protein. J Biol Chem. 2011, 286(26):22707-10. PubMed PMID: 21566134; PubMed Central PMCID: PMC3123037.
• Martin-Orozco N, Li Y, Wang Y, Liu S, Hwu P, Liu YJ, Dong C, Radvanyi L.Melanoma cells express ICOS ligand to promote the activation and expansion of T-regulatory cells. Cancer Res. 2010, 70(23):9581-90. 
• Chacon-Salinas R, Limon-Flores AY, Chavez-Blanco AD, Gonzalez-Estrada A, Ullrich SE. Mast cell-derived IL-10 suppresses germinal center formation by affecting T follicular helper cell function. J Immunol. 2011, 186(1):25-31. .
• Chang SH, Chung Y, Dong C. Vitamin D suppresses Th17 cytokine production by inducing C/EBP homologous protein (CHOP) expression. J Biol Chem. 2010, 285(50):38751-5. 
• Fukunaga A, Khaskhely NM, Ma Y, Sreevidya CS, Taguchi K, Nishigori C, Ullrich SE. Langerhans cells serve as immunoregulatory cells by activating NKT cells. J Immunol. 2010, 185(8):4633-40. .
• Reynolds JM, Pappu BP, Peng J, Martinez GJ, Zhang Y, Chung Y, Ma L, Yang XO, Nurieva RI, Tian Q, Dong C. Toll-like receptor 2 signaling in CD4(+) T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease. Immunity. 2010, 32(5):692-702. 
• Peng J, Yang XO, Chang SH, Yang J, Dong C. IL-23 signaling enhances Th2 polarization and regulates allergic airway inflammation. Cell Res. 2010, 20(1):62-71. 
• Martin-Orozco N, Muranski P, Chung Y, Yang XO, Yamazaki T, Lu S, Hwu P, Restifo NP, Overwijk WW, Dong C. T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity. 2009, 31(5):787-98. 
• Nurieva R, Yang XO, Chung Y, Dong C. Cutting edge: in vitro generated Th17 cells maintain their cytokine expression program in normal but not lymphopenic hosts. J Immunol. 2009, 182(5):2565-8. 
• Martin-Orozco N, Chung Y, Chang SH, Wang YH, Dong C. Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells. Eur J Immunol. 2009, 39(1):216-24. 
• Yamazaki T, Yang XO, Chung Y, Fukunaga A, Nurieva R, Pappu B, Martin-Orozco N, Kang HS, Ma L, Panopoulos AD, Craig S, Watowich SS, Jetten AM, Tian Q, Dong C. CCR6 regulates the migration of inflammatory and regulatory T cells. J Immunol. 2008, 181(12):8391-401. .
• Byrne SN, Limon-Flores AY, Ullrich SE. Mast cell migration from the skin to the draining lymph nodes upon ultraviolet irradiation represents a key step in the induction of immune suppression. J Immunol. 2008, 180(7):4648-55. .
• Fukunaga A, Khaskhely NM, Sreevidya CS, Byrne SN, Ullrich SE. Dermal dendritic cells, and not Langerhans cells, play an essential role in inducing an immune response. J Immunol. 2008, 180(5):3057-64.

Vaccines

Overview:  Several CCIR members are developing therapeutic vaccines for different types of cancer and finding ways to improve their efficacy.  The ability to generate a strong immune response in vivo through vaccination is critical to the successful induction of immunity against infectious agents and cancer. Three randomized clinical trials have recently demonstrated the benefits of vaccination for patients with melanoma, lymphoma and prostate cancer. Drs. Hwu and Kwak were leaders in two of these pivotal trials (Schwartzentruber DJ, N Engl Med. 2011;Schuster SJ, J Clin Oncol. 2011).  In addition, the availability of agents that are capable of enhancing immune responses, such as TLR agonists, cytokines, and immunomodulatory antibodies, underscores the importance of developing rational combinations of agents to optimally activate cellular and humoral immunity against pathogens and cancer.  

Some highlights from Fiscal Year 2013 include: 
• A recent study demonstrated that lenalidomide, in addition to its own cytotoxic effects on tumor cells, can also serve as an immune adjuvant in combination with vaccine therapy, as demonstrated in tumor-bearing mice, via two proposed mechanisms: effect on T-cell activation to boost adaptive antitumor immunity and amelioration of tumor-induced immune suppression (Sakamaki I, Leukemia, 2013)
• Vaccination with Dickkopf-1 (DKK1), broadly expressed in myeloma cells but highly restricted in normal tissues, was shown to protect mice from developing myeloma and also shown to be therapeutic against established myeloma, thus providing strong and direct evidence to support the application of DKK1-based immunotherapy in myeloma patients (Qian J, Blood, 2012)
• A study recently published in Nature Medicine demonstrated that peptide/IFA-based vaccination sites may outcompete tumor sites for T cell recognition, chemokine production, T cell accumulation and tissue destruction; these findings may help explain the typically limited clinical benefit of antigen-specific CD8+ T cells induced by a widely used class of cancer vaccines (Hailemichael Y, Nat Med. 2013)
• The Annual Texas Cancer Vaccine Symposium was organized and sponsored by the CCIR, held in the S. Campus Research Building at MD Anderson Cancer Center on January 13, 2014. Over 100 participants attended the Symposium, representing more than 10 different institutions throughout the state of Texas.  The Symposium included 14 oral presentations as well as a poster session, forming the basis for many new collaborations and grant opportunities.

Additional Relevant Publications:

• Chung Y, Lee YH, Zhang Y, Martin-Orozco N, Yamazaki T, Zhou D, Kang CY, Hwu P, Kwak LW, Dong C. T cells and T cell tumors efficiently generate antigen-specific cytotoxic T cell immunity when modified with an NKT ligand. Oncoimmunology. 2012, 1(2):141-151. 
• Weng J, Rawal S, Chu F, Park HJ, Sharma R, Delgado DA, Fayad L, Fanale M, Romaguera J, Luong A, Kwak LW, Neelapu SS. TCL1: a shared tumor-associated antigen for immunotherapy against B-cell lymphomas. Blood. 2012, 120(8):1613-23. 
• Hong S, Qian J, Li H, Yang J, Lu Y, Zheng Y, Yi Q. CpG or IFN-α are more potent adjuvants than GM-CSF to promote anti-tumor immunity following idiotype vaccine in multiple myeloma. Cancer Immunol Immunother. 2012, 61(4):561-71.
• Rodriguez-Cruz TG, Liu S, Khalili JS, Whittington M, Zhang M, Overwijk W, Lizee G. Natural splice variant of MHC class I cytoplasmic tail enhances dendritic cell-induced CD8+ T cell responses and boosts anti-tumor immunity. PLoS One. 2011; 6(8):e22939. 
• Courtney AN, Thapa P, Singh S, Wishahy AM, Zhou D, Sastry J. Intranasal but not intravenous delivery of the adjuvant α-galactosylceramide permits repeated stimulation of natural killer T cells in the lung. Eur J Immunol. 2011, 41(11):3312-22. 
• Weng J, Cha SC, Matsueda S, Alatrash G, Popescu MS, Yi Q, Molldrem JJ, Wang M, Neelapu SS, Kwak LW. Targeting human B-cell malignancies through Ig light chain-specific cytotoxic T lymphocytes. Clin Cancer Res. 2011, 17(18):5945-52. 
• Singh A, Qin H, Fernandez I, Wei J, Lin J, Kwak LW, Roy K. An injectable synthetic immune-priming center mediates efficient T cell class switching and T-helper 1 response against B cell lymphoma. J Control Release. 2011, 155(2):184-92. 
• Lou Y, Liu C, Lizee G, Peng W, Xu C, Ye Y, Rabinovich BA, Hailemichael Y, Gelbard A, Zhou D, Overwijk WW, Hwu P. Antitumor activity mediated by CpG: the route of administration is critical. J Immunother. 2011, 34(3):279-88. 
• Qin H, Cha SC, Neelapu SS, Liu C, Wang YH, Wei J, Qin XF, Liu YJ, Kwak LW.Generation of an immune microenvironment as a novel mechanism for myotoxins to potentiate genetic vaccines. Vaccine. 2010, 28(50):7970-8. 
• Yi Q, Szmania S, Freeman J, Qian J, Rosen NA, Viswamitra S, Cottler-Fox M, Barlogie B, Tricot G, van Rhee F. Optimizing dendritic cell-based immunotherapy in multiple myeloma: intranodal injections of idiotype-pulsed CD40 ligand-matured vaccines led to induction of type-1 and cytotoxic T cell immune responses in patients. Br J Haematol. 2010, 150(5):554-64. 
• Qin H, Nehete PN, He H, Nehete B, Buchl S, Cha SC, Sastry JK, Kwak LW. Prime-boost vaccination using chemokine-fused gp120 DNA and HIV envelope peptides activates both immediate and long-term memory cellular responses in rhesus macaques. J Biomed Biotechnol. 2010, 2010:860160. 
• He H, Courtney AN, Wieder E, Sastry KJ. Multicolor flow cytometry analyses of cellular immune response in rhesus macaques. J Vis Exp. 2010, (38). 
• Frasca L, Stonier SW, Overwijk WW, Schluns KS. Differential mechanisms of memory CD8 T cell maintenance by individual myeloid cell types. J Leukoc Biol. 2010, 88(1):69-78. 
• Weaver EA, Nehete PN, Nehete BP, Buchl SJ, Palmer D, Montefiori DC, Ng P,Sastry KJ, Barry MA. Protection against Mucosal SHIV Challenge by Peptide and Helper-Dependent Adenovirus Vaccines. Viruses. 2009, 1(3):920. 
• Qin H, Cha SC, Neelapu SS, Lou Y, Wei J, Liu YJ, Kwak LW. Vaccine site inflammation potentiates idiotype DNA vaccine-induced therapeutic T cell-, and not B cell-, dependent antilymphoma immunity. Blood. 2009, 114(19):4142-9. 
• Qian J, Hong S, Wang S, Zhang L, Sun L, Wang M, Yang J, Kwak LW, Hou J, Yi Q. Myeloma cell line-derived, pooled heat shock proteins as a universal vaccine for immunotherapy of multiple myeloma. Blood. 2009,  114(18):3880-9. .
• Sikora AG, Jaffarzad N, Hailemichael Y, Gelbard A, Stonier SW, Schluns KS, Frasca L, Lou Y, Liu C, Andersson HA, Hwu P, Overwijk WW. IFN-alpha enhances peptide vaccine-induced CD8+ T cell numbers, effector function, and antitumor activity. J Immunol. 2009, 182(12):7398-407. 
• Weaver EA, Nehete PN, Buchl SS, Senac JS, Palmer D, Ng P, Sastry KJ, Barry MA. Comparison of replication-competent, first generation, and helper-dependent adenoviral vaccines. PLoS One. 2009, 4(3):e5059. 
• Courtney AN, Nehete PN, Nehete BP, Thapa P, Zhou D, Sastry KJ. Alpha-galactosylceramide is an effective mucosal adjuvant for repeated intranasal or oral delivery of HIV peptide antigens. Vaccine. 2009, 27(25-26):3335-41.
• Thapa P, Zhang G, Xia C, Gelbard A, Overwijk WW, Liu C, Hwu P, Chang DZ, Courtney A, Sastry JK, Wang PG, Li C, Zhou D. Nanoparticle formulated alpha-galactosylceramide activates NKT cells without inducing anergy. Vaccine. 2009, 27(25-26):3484-8. 
• Hong S, Qian J, Yang J, Li H, Kwak LW, Yi Q. Roles of idiotype-specific T cells in myeloma cell growth and survival: Th1 and CTL cells are tumoricidal while Th2 cells promote tumor growth. Cancer Res. 2008, 68(20):8456-64. 
• Stonier SW, Ma LJ, Castillo EF, Schluns KS. Dendritic cells drive memory CD8 T cell homeostasis via IL-15 transpresentation. Blood. 2008, 112(12):4546-54.
• Liu C, Lou Y, Lizee G, Qin H, Liu S, Rabinovich B, Kim GJ, Wang YH, Ye Y, Sikora AG, Overwijk WW, Liu YJ, Wang G, Hwu P. Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T cell cross-priming and tumor regression in mice. J Clin Invest. 2008, 118(3):1165-75. 
• Nehete PN, Nehete BP, Hill L, Manuri PR, Baladandayuthapani V, Feng L, Simmons J, Sastry KJ. Selective induction of cell-mediated immunity and protection of rhesus macaques from chronic SHIV(KU2) infection by prophylactic vaccination with a conserved HIV-1 envelope peptide-cocktail. Virology. 2008, 370(1):130-41.

Antibody and T-cell therapeutics

Overview:  Several CCIR members are developing antibody and T cell therapies for different types of cancer and finding ways to improve their efficacy.  Much progress has been made recently in the clinical use of antibodies and T cells for cancer therapeutics. Antibodies that target immune checkpoints have been effective in patients with metastatic cancer, and one of these, anti-CTLA-4, pioneered by Dr. James Allison, a new member of the CCIR, has been FDA approved for the treatment of metastatic melanoma. Dr. Allison’s work has opened a new field of utilizing antibodies against immune checkpoints, and other similar antibodies, such as anti-PD1 antibody, have been found to be effective against melanoma as well as renal cancer and lung cancer in patients with metastatic disease. In addition, antibodies that block regulatory immune cell function or activate co-stimulatory molecules, such as anti-OX40, have significant promise. Another modality that has shown significant promise in the clinic is the adoptive transfer of activated T cells. This therapy has been effective in patients with metastatic melanoma, and with genetic engineering using chimeric antigen receptor genes (CAR), T cells can be armed to attack other common cancers, such as leukemias and lymphoma.  Clinical development of reagents or strategies as a form of immunotherapy and advancement of cancer immunotherapies are ongoing.

Some highlights from the past year include:  
• A phase 2 clinical study, completed at the MD Anderson Cancer Center, showed that the combination of pidilizumab plus rituximab is well tolerated and active in patients with relapsed follicular lymphoma, suggesting that immune checkpoint blockade is worthy of further study in follicular lymphoma (Westin JR, Lancet Oncol. 2014)
• Treatment of patient-derived chemotherapy-resistant acute myelogenous leukemia with a novel T cell receptor-like mAb to PR1/HLA-A2, developed by CCIR investigators, eliminated leukemia stem cells in a xenograft model (Sergeeva A, In Press, 2014)
• A preclinical study found that adoptive T-cell transfer (ACT) with melanoma-specific T cells was much more effective in the context of concurrent BRAF inhibition, which led to increased T-cell infiltration of tumors that could be attributed largely to decreased VEGF production by the tumor cells (Liu CW, Clin Cancer Res. 2012)

Additional Relevant Publications:

• Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y, Yagita H, Overwijk WW, Lizée G, Radvanyi L, Hwu P. PD-1 Blockade Enhances T-cell Migration to Tumors by Elevating IFN-γ Inducible Chemokines. Cancer Res. 2012, 72(20):5209-18. 
• Zhang M, Maiti S, Bernatchez C, Huls H, Rabinovich B, Champlin RE, Vence LM, Hwu P, Radvanyi L, Cooper LJ. A new approach to simultaneously quantify both TCR α- and β-chain diversity after adoptive immunotherapy. Clin Cancer Res. 2012, 18(17):4733-42. 
• Torikai H, Reik A, Liu PQ, Zhou Y, Zhang L, Maiti S, Huls H, Miller JC, Kebriaei P, Rabinovitch B, Lee DA, Champlin RE, Bonini C, Naldini L, Rebar EJ, Gregory PD, Holmes MC, Cooper LJ. A foundation for universal T cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR. Blood. 2012, 119(24):5697-705. 
• Liu C, Lewis CM, Lou Y, Xu C, Peng W, Yang Y, Gelbard AH, Lizee G, Zhou D, Overwijk WW, Hwu P. Agonistic antibody to CD40 boosts the antitumor activity of adoptively transferred T cells in vivo. J Immunother. 2012, 35(3):276-82. 
• O'Connor CM, Sheppard S, Hartline CA, Huls H, Johnson M, Palla SL, Maiti S, Ma W, Davis RE, Craig S, Lee DA, Champlin R, Wilson H, Cooper LJ. Adoptive T cell therapy improves treatment of canine non-Hodgkin lymphoma post chemotherapy. Sci Rep. 2012, 2:249. 
• Denman CJ, Senyukov VV, Somanchi SS, Phatarpekar PV, Kopp LM, Johnson JL, Singh H, Hurton L, Maiti SN, Huls MH, Champlin RE, Cooper LJ, Lee DA.Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS One. 2012, 7(1):e30264. 
• Kebriaei P, Huls H, Jena B, Munsell M, Jackson R, Lee DA, Hackett PB, Rondon G, Shpall E, Champlin RE, Cooper LJ. Infusing CD19-directed T cells to augment disease control in patients undergoing autologous hematopoietic stem-cell transplantation for advanced B-lymphoid malignancies. Hum Gene Ther. 2012, 23(5):444-50. 
• Roszik J, Rabinovich B, Cooper LJ. Imaging of T cells expressing chimeric antigen receptors. Immunotherapy. 2011, 3(12):1411-4. 
• Huang G, Yu L, Cooper LJ, Hollomon M, Huls H, Kleinerman ES. Genetically modified T cells targeting interleukin-11 receptor a-chain kill human osteosarcoma cells and induce the regression of established osteosarcoma lung metastases. Cancer Res. 2012, 72(1):271-81. .
• Joseph RW, Peddareddigari VR, Liu P, Miller PW, Overwijk WW, Bekele NB, Ross MI, Lee JE, Gershenwald JE, Lucci A, Prieto VG, McMannis JD, Papadopoulos N, Kim K, Homsi J, Bedikian A, Hwu WJ, Hwu P, Radvanyi LG. Impact of clinical and pathologic features on tumor-infiltrating lymphocyte expansion from surgically excised melanoma metastases for adoptive T cell therapy. Clin Cancer Res. 2011, 17(14):4882-91. 
• Singh H, Figliola MJ, Dawson MJ, Huls H, Olivares S, Switzer K, Mi T, Maiti S, Kebriaei P, Lee DA, Champlin RE, Cooper LJ. Reprogramming CD19-specific T cells with IL-21 signaling can improve adoptive immunotherapy of B-lineage malignancies. Cancer Res. 2011, 71(10):3516-27. 
• Cao Y, Lan Y, Qian J, Zheng Y, Hong S, Li H, Wang M, Kwak LW, Lin D, Yang J, Yi Q. Targeting cell surface β2-microglobulin by pentameric IgM antibodies. Br J Haematol. 2011, 154(1):111-21. 
• Jin Z, Maiti S, Huls H, Singh H, Olivares S, Mates L, Izsvak Z, Ivics Z, Lee DA, Champlin RE, Cooper LJ. The hyperactive Sleeping Beauty transposase SB100X improves the genetic modification of T cells to express a chimeric antigen receptor. Gene Ther. 2011, 18(9):849-56.  
• Hernandez-Chacon JA, Li Y, Wu RC, Bernatchez C, Wang Y, Weber JS, Hwu P, Radvanyi LG. Costimulation through the CD137/4-1BB pathway protects human melanoma tumor-infiltrating lymphocytes from activation-induced cell death and enhances antitumor effector function. J Immunother. 2011, 34(3):236-50. 
• Sergeeva A, Alatrash G, He H, Ruisaard K, Lu S, Wygant J, McIntyre BW, Ma Q, Li D, St John L, Clise-Dwyer K, Molldrem JJ. An anti-PR1/HLA-A2 T cell receptor-like antibody mediates complement-dependent cytotoxicity against acute myeloid leukemia progenitor cells. Blood. 2011, 117(16):4262-72. 
• Li D, Li Y, Hernandez JA, Patenia R, Kim TK, Khalili J, Dougherty MC, Hanley PJ, Bollard CM, Komanduri KV, Hwu P, Champlin RE, Radvanyi LG, Molldrem JJ, Ma Q. Lovastatin inhibits T cell proliferation while preserving the cytolytic function of EBV, CMV, and MART-1-specific CTLs. J Immunother. 2010, 33(9):975-82. 
• Peng W, Ye Y, Rabinovich BA, Liu C, Lou Y, Zhang M, Whittington M, Yang Y, Overwijk WW, Lizée G, Hwu P. Transduction of tumor-specific T cells with CXCR2 chemokine receptor improves migration to tumor and antitumor immune responses. Clin Cancer Res. 2010, 16(22):5458-68. 
• Ma Q, Wang C, Jones D, Quintanilla KE, Li D, Wang Y, Wieder ED, Clise-Dwyer K, Alatrash G, Mj Y, Munsell MF, Lu S, Qazilbash MH, Molldrem JJ. Adoptive transfer of PR1 cytotoxic T lymphocytes associated with reduced leukemia burden in a mouse acute myeloid leukemia xenograft model. Cytotherapy. 2010, 12(8):1056-62. 
• Kanodia S, Wieder E, Lu S, Talpaz M, Alatrash G, Clise-Dwyer K, Molldrem JJ.PR1-specific T cells are associated with unmaintained cytogenetic remission of chronic myelogenous leukemia after interferon withdrawal. PLoS One. 2010, 5(7):e11770. 
• Choi Y, Yuen C, Maiti SN, Olivares S, Gibbons H, Huls H, Raphael R, Killian TC, Stark DJ, Lee DA, Torikai H, Monticello D, Kelly SS, Kebriaei P, Champlin RE, Biswal SL, Cooper LJ. A high throughput microelectroporation device to introduce a chimeric antigen receptor to redirect the specificity of human T cells. Biomed Microdevices. 2010, 12(5):855-63. 
• Davies JK, Singh H, Huls H, Yuk D, Lee DA, Kebriaei P, Champlin RE, Nadler LM, Guinan EC, Cooper LJ. Combining CD19 redirection and alloanergization to generate tumor-specific human T cells for allogeneic cell therapy of B-cell malignancies. Cancer Res. 2010, 70(10):3915-24. 
• Liu S, Etto T, Rodriguez-Cruz T, Li Y, Wu C, Fulbright OJ, Hwu P, Radvanyi L, Lizée G. TGF-beta1 induces preferential rapid expansion and persistence of tumor antigen-specific CD8+ T cells for adoptive immunotherapy. J Immunother. 2010, 33(4):371-81. 
• Hurton LV, Siddik RI, Singh H, Olivares S, Rabinovich BA, Tian R, Mojsilovic D, Hildebrand W, Lee DA, Kelly SS, Champlin R, Shpall EJ, Fernandez-Viña M, Cooper LJ. Identifying candidate allogeneic NK-cell donors for hematopoieticstem-cell transplantation based on functional phenotype. Leukemia. 2010, 24(5):1059-62. 
• Li Y, Liu S, Hernandez J, Vence L, Hwu P, Radvanyi L. MART-1-specific melanoma tumor-infiltrating lymphocytes maintaining CD28 expression have improved survival and expansion capability following antigenic restimulation in vitro. J Immunol. 2010, 184(1):452-65.
• Manuri PV, Wilson MH, Maiti SN, Mi T, Singh H, Olivares S, Dawson MJ, Huls H, Lee DA, Rao PH, Kaminski JM, Nakazawa Y, Gottschalk S, Kebriaei P, Shpall EJ, Champlin RE, Cooper LJ. piggyBac transposon/transposase system to generate CD19-specific T cells for the treatment of B-lineage malignancies. Hum Gene Ther. 2010, 21(4):427-37. .
• Yang J, Cao Y, Hong S, Li H, Qian J, Kwak LW, Yi Q. Human-like mouse models for testing the efficacy and safety of anti-beta2-microglobulin monoclonal antibodies to treat myeloma. Clin Cancer Res. 2009, 15(3):951-9. 
• Singh H, Najjar AM, Olivares S, Nishii R, Mukhopadhyay U, Alauddin M, Manuri PR, Huls H, Lee DA, Dotti G, Bollard C, Simmons PJ, Shpall EJ, Champlin RE,Gelovani JG, Cooper LJ. PET imaging of T cells derived from umbilical cord blood. Leukemia. 2009, 23(3):620-2. 
• Voorhees PM, Chen Q, Small GW, Kuhn DJ, Hunsucker SA, Nemeth JA, Orlowski RZ. Targeted inhibition of interleukin-6 with CNTO 328 sensitizes pre-clinical models of multiple myeloma to dexamethasone-mediated cell death. Br J Haematol. 2009, 145(4): 481-90.
• Wang M, Sun L, Qian J, Han X, Zhang L, Lin P, Cai Z, Yi Q. Cyclin D1 as a universally expressed mantle cell lymphoma-associated tumor antigen for immunotherapy. Leukemia. 2009, 23(7): 1320-8.
• Wang Y, Li D, Jones D, Bassett R, Sale GE, Khalili J, Komanduri KV, Couriel DR, Champlin RE, Molldrem JJ, Ma Q. Blocking LFA-1 activation with lovastatin prevents graft-versus-host disease in mouse bone marrow transplantation. Biol Blood Marrow Transplant. 2009, 5(12): 1513-22.
• Rabinovich BA, Ye Y, Etto T, Chen JQ, Levitsky HI, Overwijk WW, Cooper LJ, Gelovani J, Hwu P. Visualizing fewer than 10 mouse T cells with an enhanced firefly luciferase in immunocompetent mouse models of cancer. Proc Natl Acad Sci U S A. 2008, 105(38):14342-6. 
• Singh H, Manuri PR, Olivares S, Dara N, Dawson MJ, Huls H, Hackett PB, Kohn DB, Shpall EJ, Champlin RE, Cooper LJ. Redirecting specificity of T cell populations for CD19 using the Sleeping Beauty system. Cancer Res. 2008, 68(8):2961-71. 
• Lee ST, Liu S, Radvanyi L, Sukhumalchandra P, Molldrem JJ, Wieder ED, Hwu P, Liu YJ, Kwak LW, Lizee G, Neelapu SS. A novel strategy for rapid and efficient isolation of human tumor-specific CD4(+) and CD8(+) T cell clones. J Immunol Methods. 2008, 331(1-2):13-26.