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 inhibitiry scFv antibodies targeting fibroblast activation protein utilizing phage display functional screens.  FASEB J. 2013 Feb;27(2):581-589.  PMID: 23104982

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. International Journal of Cancer. 2009 Nov. PMID: 19937796

Bai J, Demirjian A, Sui J, Marasco WA and 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):1245-1253. PMID: 16904634

Yuan Q-A, Simmons HH, Robinson MK, Russeva M, Marasco WA and Adams GP. The development of engineered antibodies specific for the Műllerian inhibiting substance type II receptor (MISIIR) – A promising candidate for the targeted therapy of ovarian cancer. Mol Cancer Ther 2006 5(8):2096-2105. PMID: 16928831

Song E, Zhu P, Lee S-K, Chowdhury D, Kussman S, Dykxhoorn D, Feng Y, Palliser D, Weiner DB, Shankar P, Marasco WA and Lieberman J. Antibody-mediated in vivo delivery of short interfering RNAs via cell surface receptors. Nature Biotechnol. 2005 Jun;23(6):709-17. Epub 2005 May 22 PMID: 15908939

Bai J, Sui J, Demirjian A, Vollmer CM, Marasco WA and Callery MP. Predominant Bcl-Xl knockdown disables anti-apoptotic mechanisms: TRAIL-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, and Marasco WA. Single-chain antibody mediated-gene delivery into ErbB2 positive human breast cancer cells. Cancer Gene Ther 2001;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.

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Hypothetical mechanisms of mAb2-3-mediated immunotherapy. mAb2-3 may form a barrier preventing tumor cells secreting CCL22 to chemotactically attract CCR4+ regulatory T cells (Tregs).  This may result in restoration of tumor immune surveillance through tumor infiltrating effector T cells (Teffs) due to blockade of Tregs accumulation in the tumor microenvironment. mAb2-3 also appears to specifically bind to CCR4+ Teffs, including naïve and central memory T cells, resulting in re-establishment of Teff activity through release of pro-inflammatory cytokines.

In the Media Dec 18, 2012: A two-fisted blow against a deadly cancer   pdf 

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 Sep 4 2012 | doi:10.1371/journal/pone.0044455

Chang DK, Sui J, Geng S, Muvaffak A, Bai M, Fuhlbrigge RC, Lo AS,Yammanuru A, Hubbard L, Sheehan J, Campbell JJ, Zhu Q, Kupper TS and 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 Aug 6.  PMID:22869555 

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.

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

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

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. PMID: 27119093

Xu C, Lo A, Yammanuru A, Tallarico AS, Brady K, Murakami A, Barteneva N, Zhu QK, and 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 

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 Mar 10:1-12. PMID: 26963739 

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 and Marasco WA. Anti-CCR4 antibody enhances anti-tumor immunity by modulating tumor-infiltrating Tregs in an ovarian cancer xenograft humanized mouse model. OncoImmunol. 2015 Dec 10;5(3):e1090075. PMID: 27141347