CANCER IMMUNOTHERAPY
Among the most challenging questions in immunology is understanding how the immune system affects cancer development and progression. We now realize that the immune system plays a dual role in cancer. On the one hand, it can suppress tumor growth by destroying cancer cells or inhibiting their outgrowth while on the other hand it can also promote tumor progression either by selecting for tumor cells that are more fit to survive or by establishing conditions within the tumor microenvironment that facilitate tumor outgrowth. With this new understanding, antibody-based cancer immunotherapy has progressed well beyond just isolating human antibodies against tumor-associated antigens but now also involves reversing the immune dysregulation that evades the surveillance of our immune systems. We can also engineer the Fc region of human antibodies to increase antibody-dependent cellular cytotoxicity (ADCC) and tailor their serum half-life. Read more about the ongoing projects in Cutaneous T-Cell Lymphoma (CTCL), Renal Cell Carcinoma (RCC), Chronic Lymphocytic Leukemia (CLL) and Immunopotentiating Agents for Cancer Vaccines.
Zhang J, Valianou M, Simmons H, Robinson MK, Lee HO, Mullins SR, Marasco WA, Adams GP, Weiner LM, Cheng JD. Identification of inhibitory scFv antibodies targeting fibroblast activation protein utilizing phage display functional screens. FASEB J. 2013 Feb;27(2):581-9. Epub 2012 Oct 26. PMID: 23104982. PMCID: PMC3545529.
Kuan CT, Srivastava N, McLendon RE, Marasco WA, Zalutsky MR, Bigner DD. Recombinant single-chain variable fragment antibodies against extracellular epitopes of human multidrug resistance protein MRP3 for targeting malignant gliomas. Int J Cancer. 2010 Aug 1;127(3):598-611. PMID: 19937796. PMCID: PMC2878888.
Bai J, Demirjian A, Sui J, Marasco W, Callery MP. Histone deacetylase inhibitor trichostatin A and proteasome inhibitor PS-341 synergistically induce apoptosis in pancreatic cancer cells. Biochem Biophys Res Commun. 2006 Oct 6;348(4):1245-53. Epub 2006 Aug 7. PMID: 16904634.
Yuan QA, Simmons HH, Robinson MK, Russeva M, Marasco WA, Adams GP. Development of engineered antibodies specific for the Müllerian inhibiting substance type II receptor: a promising candidate for targeted therapy of ovarian cancer. Mol Cancer Ther. 2006 Aug;5(8):2096-105. PMID: 16928831.
Song E, Zhu P, Lee SK, Chowdhury D, Kussman S, Dykxhoorn DM, Feng Y, Palliser D, Weiner DB, Shankar P, Marasco WA, Lieberman J. Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat Biotechnol. 2005 Jun;23(6):709-17. Epub 2005 May 22. PMID: 15908939.
Bai J, Sui J, Demirjian A, Vollmer CM Jr, Marasco W, Callery MP. Predominant Bcl-XL knockdown disables antiapoptotic mechanisms: tumor necrosis factor-related apoptosis-inducing ligand-based triple chemotherapy overcomes chemoresistance in pancreatic cancer cells in vitro. Cancer Res. 2005 Mar 15;65(6):2344-52. PMID: 15781649.
Li X, Stuckert P, Bosch I, Marks JD, Marasco WA. Single-chain antibody-mediated gene delivery into ErbB2-positive human breast cancer cells. Cancer Gene Ther. 2001 Aug;8(8):555-65. PMID: 11571533.
Zhang J, Valianou M, Simmons H, Robinson MK, Lee HO, Mullins SR, Marasco WA, Adams GP, Weiner LM, Cheng JD. Identification of inhibitory scFv antibodies targeting fibroblast activation protein utilizing phage display functional screens. FASEB J. 2013 Feb;27(2):581-9. Epub 2012 Oct 26. PMID: 23104982. PMCID: PMC3545529.
Kuan CT, Srivastava N, McLendon RE, Marasco WA, Zalutsky MR, Bigner DD. Recombinant single-chain variable fragment antibodies against extracellular epitopes of human multidrug resistance protein MRP3 for targeting malignant gliomas. Int J Cancer. 2010 Aug 1;127(3):598-611. PMID: 19937796. PMCID: PMC2878888.
Bai J, Demirjian A, Sui J, Marasco W, Callery MP. Histone deacetylase inhibitor trichostatin A and proteasome inhibitor PS-341 synergistically induce apoptosis in pancreatic cancer cells. Biochem Biophys Res Commun. 2006 Oct 6;348(4):1245-53. Epub 2006 Aug 7. PMID: 16904634.
Yuan QA, Simmons HH, Robinson MK, Russeva M, Marasco WA, Adams GP. Development of engineered antibodies specific for the Müllerian inhibiting substance type II receptor: a promising candidate for targeted therapy of ovarian cancer. Mol Cancer Ther. 2006 Aug;5(8):2096-105. PMID: 16928831.
Song E, Zhu P, Lee SK, Chowdhury D, Kussman S, Dykxhoorn DM, Feng Y, Palliser D, Weiner DB, Shankar P, Marasco WA, Lieberman J. Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat Biotechnol. 2005 Jun;23(6):709-17. Epub 2005 May 22. PMID: 15908939.
Bai J, Sui J, Demirjian A, Vollmer CM Jr, Marasco W, Callery MP. Predominant Bcl-XL knockdown disables antiapoptotic mechanisms: tumor necrosis factor-related apoptosis-inducing ligand-based triple chemotherapy overcomes chemoresistance in pancreatic cancer cells in vitro. Cancer Res. 2005 Mar 15;65(6):2344-52. PMID: 15781649.
Li X, Stuckert P, Bosch I, Marks JD, Marasco WA. Single-chain antibody-mediated gene delivery into ErbB2-positive human breast cancer cells. Cancer Gene Ther. 2001 Aug;8(8):555-65. PMID: 11571533.
Cutaneous T-Cell Lymphoma (CTCL)
Cutaneous T-cell lymphoma (CTCL) defines a heterogeneous group of neoplastic disorders characterized by clonally derived and skin-homing malignant T-cells. The mechanisms involved in tumor homing to the skin are still not fully elucidated, however there is growing evidence that CC chemokine receptor 4 (CCR4) which is expressed at uniformly high levels on skin-homing T-cells is involved. Advanced CTCL is lethal and incurable, and current therapies are only palliative. We are investigating whether a humanized anti-CCR4 Mab might represent a novel molecular targeting approach for immunotherapy against relapsed or refractory T-cell lymphomas.
Han T, Abdel-Motal UM, Chang DK, Sui J, Muvaffak A, Campbell J, Zhu Q, Kupper TS, Marasco WA. Human anti-CCR4 minibody gene transfer for the treatment of cutaneous T-cell lymphoma. PLoS One. 2012;7(9):e44455. Epub 2012 Sept 4. PMID: 22973452. PMCID: PMC3433438.
Chang DK, Sui J, Geng S, Muvaffak A, Bai M, Fuhlbrigge RC, Lo A, Yammanuru A, Hubbard L, Sheehan J, Campbell JJ, Zhu Q, Kupper TS, Marasco WA. Humanization of an anti-CCR4 antibody that kills cutaneous T-cell lymphoma cells and abrogates suppression by T-regulatory cells. Mol Cancer Ther. 2012 Nov;11(11):2451-61. Epub 2012 Aug 6. PMID: 22869555. PMCID: PMC3496034.
Han T, Abdel-Motal UM, Chang DK, Sui J, Muvaffak A, Campbell J, Zhu Q, Kupper TS, Marasco WA. Human anti-CCR4 minibody gene transfer for the treatment of cutaneous T-cell lymphoma. PLoS One. 2012;7(9):e44455. Epub 2012 Sept 4. PMID: 22973452. PMCID: PMC3433438.
Chang DK, Sui J, Geng S, Muvaffak A, Bai M, Fuhlbrigge RC, Lo A, Yammanuru A, Hubbard L, Sheehan J, Campbell JJ, Zhu Q, Kupper TS, Marasco WA. Humanization of an anti-CCR4 antibody that kills cutaneous T-cell lymphoma cells and abrogates suppression by T-regulatory cells. Mol Cancer Ther. 2012 Nov;11(11):2451-61. Epub 2012 Aug 6. PMID: 22869555. PMCID: PMC3496034.
Renal Cell Carcinoma (RCC) and other hypoxic solid tumors
We have developed a panel of human Mabs against the tumor associated antigen, carbonic anhydrase (CAIX). CAIX is overexpressed on essentially all clear cell-type of RCCs. Interesting, CAIX is under the control of hypoxia-inducible factor (HIF-1α) and as a result, a large number of different solid tumors overexpress this protein. We are currently involved in pre-clinical studies to evaluate these Mabs for the immunotherapy of RCC and other solid tumors.
Wang Y, Buck A, Piel B, Zerefa L, Murugan N, Coherd CD, Miklosi AG, Johal H, Bastos RN, Huang K, Ficial M, Laimon YN, Signoretti S, Zhong Z, Hoang SM, Kastrunes GM, Grimaud M, Fayed A, Yuan HC, Nguyen QD, Thai T, Ivanova EV, Paweletz CP, Wu MR, Choueiri TK, Wee JO, Freeman GJ, Barbie DA, Marasco WA. Affinity fine-tuning anti-CAIX CAR-T cells mitigate on-target off-tumor side effects. Mol Cancer. 2024 Mar 16;23(1):56. doi: 10.1186/s12943-024-01952-w. PMID: 38491381; PMCID: PMC10943873.
Wang Y, Cho JW, Kastrunes G, Buck A, Razimbaud C, Culhane AC, Sun J, Braun DA, Choueiri TK, Wu CJ, Jones K, Nguyen QD, Zhu Z, Wei K, Zhu Q, Signoretti S, Freeman GJ, Hemberg M, Marasco WA. Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model. iScience. 2024 Jan 15;27(2):108879. doi: 10.1016/j.isci.2024.108879. PMID: 38327771; PMCID: PMC10847687.
Wang Y, Cho JW, Kastrunes G, Buck A, Razimbaud C, Culhane AC, Sun J, Braun DA, Choueiri TK, Wu CJ, Jones K, Nguyen QD, Zhu Z, Wei K, Zhu Q, Signoretti S, Freeman GJ, Hemberg M, Marasco WA. Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model. iScience. 2024 Jan 15;27(2):108879. doi: 10.1016/j.isci.2024.108879. PMID: 38327771; PMCID: PMC10847687.
Wang Y, Buck A, Grimaud M, Culhane AC, Kodangattil S, Razimbaud C, Bonal DM, Nguyen QD, Zhu Z, Wei K, O'Donnell ML, Huang Y, Signoretti S, Choueiri TK, Freeman GJ, Zhu Q, Marasco WA. Anti-CAIX BBζ CAR4/8 T cells exhibit superior efficacy in a ccRCC mouse model. Mol Ther Oncolytics. 2021 Dec 31. PMID: 35118195; PMCID: PMC8792103.
Suarez ER, Chang DK, Sun J, Sui J, Freeman GJ, Signoretti S, Zhu Q, Marasco WA. Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model. Oncotarget. 2016 Apr 29. PMID: 27145284. PMCID: PMC5085160.
Chang DK, Moniz RJ, Xu Z, Sun J, Signoretti S, Zhu Q, Marasco WA. Human anti-CAIX antibodies mediate immune cell inhibition of renal cell carcinoma in vitro and in a humanized mouse model in vivo. Mol Cancer. 2015 Jun 11;14:119. PMID: 26062742. PMCID: PMC4464115.
Lo AS, Xu C, Murakami A, Marasco WA. Regression of established renal cell carcinoma in nude mice using lentivirus-transduced human T cells expressing a human anti-CAIX chimeric antigen receptor. Mol Ther Oncolytics. 2014 Dec 10;1:14003. eCollection 2014. PMID: 27119093. PMCID: PMC4782938.
Xu C, Lo A, Yammanuru A, Tallarico AS, Brady K, Murakami A, Barteneva N, Zhu Q, Marasco WA. Unique biological properties of catalytic domain directed human anti-CAIX antibodies discovered through phage-display technology. PLoS One. 2010 March 10;5(3):e9625. PMID: 20224781. PMCID: PMC2835754.
Wang Y, Buck A, Piel B, Zerefa L, Murugan N, Coherd CD, Miklosi AG, Johal H, Bastos RN, Huang K, Ficial M, Laimon YN, Signoretti S, Zhong Z, Hoang SM, Kastrunes GM, Grimaud M, Fayed A, Yuan HC, Nguyen QD, Thai T, Ivanova EV, Paweletz CP, Wu MR, Choueiri TK, Wee JO, Freeman GJ, Barbie DA, Marasco WA. Affinity fine-tuning anti-CAIX CAR-T cells mitigate on-target off-tumor side effects. Mol Cancer. 2024 Mar 16;23(1):56. doi: 10.1186/s12943-024-01952-w. PMID: 38491381; PMCID: PMC10943873.
Wang Y, Cho JW, Kastrunes G, Buck A, Razimbaud C, Culhane AC, Sun J, Braun DA, Choueiri TK, Wu CJ, Jones K, Nguyen QD, Zhu Z, Wei K, Zhu Q, Signoretti S, Freeman GJ, Hemberg M, Marasco WA. Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model. iScience. 2024 Jan 15;27(2):108879. doi: 10.1016/j.isci.2024.108879. PMID: 38327771; PMCID: PMC10847687.
Wang Y, Cho JW, Kastrunes G, Buck A, Razimbaud C, Culhane AC, Sun J, Braun DA, Choueiri TK, Wu CJ, Jones K, Nguyen QD, Zhu Z, Wei K, Zhu Q, Signoretti S, Freeman GJ, Hemberg M, Marasco WA. Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model. iScience. 2024 Jan 15;27(2):108879. doi: 10.1016/j.isci.2024.108879. PMID: 38327771; PMCID: PMC10847687.
Wang Y, Buck A, Grimaud M, Culhane AC, Kodangattil S, Razimbaud C, Bonal DM, Nguyen QD, Zhu Z, Wei K, O'Donnell ML, Huang Y, Signoretti S, Choueiri TK, Freeman GJ, Zhu Q, Marasco WA. Anti-CAIX BBζ CAR4/8 T cells exhibit superior efficacy in a ccRCC mouse model. Mol Ther Oncolytics. 2021 Dec 31. PMID: 35118195; PMCID: PMC8792103.
Suarez ER, Chang DK, Sun J, Sui J, Freeman GJ, Signoretti S, Zhu Q, Marasco WA. Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model. Oncotarget. 2016 Apr 29. PMID: 27145284. PMCID: PMC5085160.
Chang DK, Moniz RJ, Xu Z, Sun J, Signoretti S, Zhu Q, Marasco WA. Human anti-CAIX antibodies mediate immune cell inhibition of renal cell carcinoma in vitro and in a humanized mouse model in vivo. Mol Cancer. 2015 Jun 11;14:119. PMID: 26062742. PMCID: PMC4464115.
Lo AS, Xu C, Murakami A, Marasco WA. Regression of established renal cell carcinoma in nude mice using lentivirus-transduced human T cells expressing a human anti-CAIX chimeric antigen receptor. Mol Ther Oncolytics. 2014 Dec 10;1:14003. eCollection 2014. PMID: 27119093. PMCID: PMC4782938.
Xu C, Lo A, Yammanuru A, Tallarico AS, Brady K, Murakami A, Barteneva N, Zhu Q, Marasco WA. Unique biological properties of catalytic domain directed human anti-CAIX antibodies discovered through phage-display technology. PLoS One. 2010 March 10;5(3):e9625. PMID: 20224781. PMCID: PMC2835754.
Chronic Lymphocytic Leukemia (CLL)
B-cell CLL is the most common type of leukemia and all available interventions e.g., radio and chemotherapy aim at controlling rather than curing the disease. One of the major limitations of the current approaches against B-CLL (and most other forms of cancer) is that they target not only the leukemic cells but also the non-cancerous cells (healthy cells). We have developed a humanized MAb which binds with high affinity to an antigen receptor found on the surface of B cells which is encoded by an antibody gene called IGHV1-69. This IGHV1-69-encoded antigen receptor is associated with advanced stages of B-CLL and a poor prognosis. An effective immunotherapy targeting this molecule may lead to a more personalized cancer therapy in comparison to current treatment methods that poorly differentiates between cancerous and non-cancerous cells.
Chang DK, Kurella VB, Biswas S, Avnir Y, Sui J, Wang X, Sun J, Wang Y, Panditrao M, Peterson E, Tallarico A, Fernandes S, Goodall M, Zhu Q, Brown JR, Jefferis R, Marasco WA. Humanized mouse G6 anti-idiotypic monoclonal antibody has therapeutic potential against IGHV1-69 germline gene-based B-CLL. MAbs. 2016 May-Jun;8(4):787-98. Epub 2016 Mar 10. PMID: 26963739. PMCID: PMC4966851.
Chang DK, Kurella VB, Biswas S, Avnir Y, Sui J, Wang X, Sun J, Wang Y, Panditrao M, Peterson E, Tallarico A, Fernandes S, Goodall M, Zhu Q, Brown JR, Jefferis R, Marasco WA. Humanized mouse G6 anti-idiotypic monoclonal antibody has therapeutic potential against IGHV1-69 germline gene-based B-CLL. MAbs. 2016 May-Jun;8(4):787-98. Epub 2016 Mar 10. PMID: 26963739. PMCID: PMC4966851.
Immunopotentiating Agents for Cancer Vaccines
Recent studies have revealed that dysfunction in the T-cell compartment is a central factor in immune dysfunction during cancer development. This immune defect has been attributed, at least in part, to T-cell exhaustion which is believed to occur when chronic cancer cell stimulation of T-cells leads to a specific state of antigen unresponsiveness. PD-1/PD1-L and IL-10 have been well described to have central roles in T-cell exhaustion, and may offer viable therapeutic targets for cancer immunotherapy as their blockade has been shown to lead to reversible inhibition of T-cell responses. We have isolated a panel of human antibodies against these and other T-cell regulatory molecules and are currently exploring their potential to serve as adjuvants to boost natural and vaccine-induced T-cell anti-cancer immunity.
Chang DK, Peterson E, Sun J, Goudie C, Drapkin RI, Liu JF, Matulonis U, Zhu Q, Marasco WA. Anti-CCR4 monoclonal antibody enhances antitumor immunity by modulating tumor-infiltrating Tregs in an ovarian cancer xenograft humanized mouse model. Oncoimmunology. 2015 Dec 10;5(3):e1090075. eCollection 2016 Mar. PMID: 27141347. PMCID: PMC4839340.
Chang DK, Peterson E, Sun J, Goudie C, Drapkin RI, Liu JF, Matulonis U, Zhu Q, Marasco WA. Anti-CCR4 monoclonal antibody enhances antitumor immunity by modulating tumor-infiltrating Tregs in an ovarian cancer xenograft humanized mouse model. Oncoimmunology. 2015 Dec 10;5(3):e1090075. eCollection 2016 Mar. PMID: 27141347. PMCID: PMC4839340.