We can enhance antibody therapy by stimulating the action of natural killer (NK) cells by a single second antibody. We can trigger a global therapeutic immune response by ?in situ vaccination?, the injection of TLR ligands directly into one tumor site. We are conducting clinical trials of both of these approaches and the early results are very promising. The addition of antibodies that block immune checkpoints make these approaches even more powerful. We will conduct preclinical and clinical projects based on these platforms. 1. Enhancing antibody therapy of cancer with a second antibody that stimulates activated NK cells. We discovered that the therapeutic activity of Rituximab and other mAbs (Traztuzumab and Cetuximab) are enhanced by the sequential addition of a second antibody against CD137 (41BB), an activation molecule on the NK killer cells. We are now leading clinical trials that test the addition of CD137 antibodies to Rituximab in patients with B cell lymphoma. Simultaneously, we are testing bispecific antibodies that bind both to the tumor and to activation markers on NK cells. 2. Therapeutic In Situ Vaccination. We demonstrated that a global therapeutic anti-tumor immune response can be triggered by the injection of TLR ligands into a single tumor site. We are conducting a phase I/II clinical trial in lymphoma patients, testing the combination of low dose XRT followed by intra-tumoral injection of both a TLR agonist and a low dose of anti CTLA4 antibody. We now have preclinical evidence for synergy between in situ vaccination and Ibrutinib, an inhibitor of BTK and ITK, a combination that works also in solid tumors. 3. The Immune Response against immunoglobulin (Ig)-derived peptides in B cell lymphoma B-cell lymphomas express a unique immunoglobulin idiotype that distinguishes malignant cells from normal B- cells. Idiotypes are ideal targets for immunotherapy because they are expressed on all the malignant cells in the patient. We discovered that patients have T cells that recognize peptides derived from idiotypes that are displayed in MHC class II molecules. Now we will design new immunotherapy directed at MHC II-idiotypes. 4. New Methods of Immune Monitoring A critical component of each of our immunotherapy projects is an intense focus on monitoring cells in the tumor microenvironment. We will obtain samples from the same tumor sites: before, during, and after the experimental therapies and analyze the cell populations by high-dimensional flow cytometry. These data sets will be compared across trials that test different modalities of immunotherapy. We will detect activated T cells in patients by novel non-invasive imaging techniques to track the effects of immunotherapies in real time .We will detect the tumor-reactive cell populations in tissue sections by Multiplexed Ion Beam Imaging (MIBI). This system can interrogate 10 or more parameters per cell with high spatial resolution on sections from FFPE embedded tissues.
We are developing new ways of treating cancer by combining treatments that target the tumor cells and treatments that target the immune system of the patient. We will combine an antibody that recognizes cancer cells with a second antibody that stimulates the NK killer cells, and we will develop a form of immune therapy called in situ vaccination, where we inject immune activating agents directly into one tumor and trigger an immune response that treats the whole body. Our work could have major public health implications because our therapies are practical and effective.
|Sagiv-Barfi, Idit; Czerwinski, Debra K; Levy, Shoshana et al. (2018) Eradication of spontaneous malignancy by local immunotherapy. Sci Transl Med 10:|
|Olsson, Niclas; Schultz, Liora M; Zhang, Lichao et al. (2018) T-Cell Immunopeptidomes Reveal Cell Subtype Surface Markers Derived From Intracellular Proteins. Proteomics 18:e1700410|
|Turaj, Anna H; Cox, Kerry L; Penfold, Christine A et al. (2018) Augmentation of CD134 (OX40)-dependent NK anti-tumour activity is dependent on antibody cross-linking. Sci Rep 8:2278|
|Frank, Matthew J; Reagan, Patrick M; Bartlett, Nancy L et al. (2018) In Situ Vaccination with a TLR9 Agonist and Local Low-Dose Radiation Induces Systemic Responses in Untreated Indolent Lymphoma. Cancer Discov 8:1258-1269|
|Kooreman, Nigel G; Kim, Youngkyun; de Almeida, Patricia E et al. (2018) Autologous iPSC-Based Vaccines Elicit Anti-tumor Responses In Vivo. Cell Stem Cell 22:501-513.e7|
|Alam, Israt S; Mayer, Aaron T; Sagiv-Barfi, Idit et al. (2018) Imaging activated T cells predicts response to cancer vaccines. J Clin Invest 128:2569-2580|
|Haabeth, Ole A W; Blake, Timothy R; McKinlay, Colin J et al. (2018) mRNA vaccination with charge-altering releasable transporters elicits human T cell responses and cures established tumors in mice. Proc Natl Acad Sci U S A 115:E9153-E9161|
|Sallets, Adrienne; Robinson, Sophie; Kardosh, Adel et al. (2018) Enhancing immunotherapy of STING agonist for lymphoma in preclinical models. Blood Adv 2:2230-2241|
|Myklebust, June H; Brody, Joshua; Kohrt, Holbrook E et al. (2017) Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling. Blood 129:759-770|