Abstract IA11: Monoclonal antibodies and in situ vaccination.
Authors: Levy Ronald 
Published: August 2015

Abstract
Traditional therapies for lymphoma have targeted features of the tumor, itself, such as cell surface molecules and intracellular signaling pathways. Increasingly, we are gaining therapeutic approaches that target the host microenvironment, and especially the host immune system. An exciting challenge is to combine these therapies in ways that are at least additive, and hopefully synergistic. We will present recent examples that combine therapies that target both the tumor and the host.
Small molecule inhibitors of survival pathways in lymphoma cells, such as B cell receptor signaling, also have effects on the immune system. A case is point is Ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase (Btk), recently approved for the treatment of CLL and MCL and with significant clinical activity in other lymphoid malignancies. Ibrutinib inhibits other members of the Tec kinase family, such as Itk, an important signaling molecule in subsets of T cells. By doing so, it can sculpt the T cell immune response and direct it against the tumor. Recent preclinical experiments indicate that Ibrutinib can enhance the T cell immune response induced by in situ vaccination as well as other immunotherapeutic maneuvers. These results imply a greater role for Ibrutinib than currently envisioned, one where it may be employed as an immune enhancer in addition to a targeted anti-tumor agent.
Abscopal tumor responses can be induced in patients with lymphoma by local in situ vaccination. CpG ologonucleotide, a ligand for a Toll-like receptor, is injected into one site of tumor and low dose radiation is directed to the same site (Brody et. al. J Clin Oncol. 2010;28(28):4324). In preclinical animal models this treatment generates an anti-tumor T cell immune response. Such T cell responses can be enhanced by additional intra-tumoral injections of antibodies against immune checkpoints, such as CTLA4 and OX40 (Marabelle et al. J Clin Invest. 2013;123(6):2447). These antibodies work by depleting the negative T regulatory cells (Tregs) in the local tumor microenvironment, unleasing T effector cells to attack tumor at distant sites. Very low doses of checkpoint antibodies can be used to avoid autoimmune adverse effects. Such combinations of low dose radiation with immune enhancing agents may change the way we employ radiotherapy in the future- to help trigger immune responses rather than to sterilize the local tumor site.
The therapeutic power of antibodies can be enhanced by stimulating ADCC, a primary mechanism of anti-tumor effect. One way to accomplish this is to target CD137, an activation molecule that appears on host NK cells after they encounter tumor cells coated by an anti-tumor antibody. In preclinical models the combination of an anti-CD20 with an anti-CD137 antibody is impressively synergistic (Kohrt et. al. Blood. 2011,117(8):2423). CD137 is also expressed on activated T cells and therefore the antibody against CD137 might also enhance an underlying host anti tumor T cell immune response. Two clinical trials are now under way to test the effect of an antibody against CD137 as a single agent and in combination with rituximab in patients with relapsed/refractory lymphoma.
Citation Format: Ronald Levy. Monoclonal antibodies and in situ vaccination. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA11.