SPORE in Lymphoma

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OVERALL PROJECT SUMMARY The long-term goal of this SPORE renewal is to develop in the laboratory, and test in the clinic novel cellular immunotherapies mediated by genetically modified immune effector cells to treat non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). We have assembled an integrated team of laboratory scientists and clinical investigators with strong track records of productive translational research supported by four shared core resources. To address the persistent challenges of suboptimal long term lymphoma control and unacceptable rates of treatment-related toxicity in lymphoma, investigators in this program have proposed three projects, each involving early-phase clinical trials. All projects address the following five distinct lines of research: 1) Use highly specific T or NKT cell immunotherapies to target multiple lymphoma antigens. This objective will be pursued in each project using either native or chimeric antigen receptors (CARs) or both. 2) Increase the potency of the T or NKT cell immunotherapies for lymphoma. This theme includes targeting multiple antigens (Projects 1 and 3), manufacturing changes to increase T cell fitness (Project 2) and adding a constitutive IL7 receptor to improve the expression and persistence of Epstein Barr Virus-specific T cells (Project 3). 3) Overcome the immune evasion tactics of lymphoma cells and their microenvironment. Project 1 will take advantage of the ability of NKT cells to overcome the immunosuppressive microenvironment to boost response rates. Project 2 will use an alloimmune defense receptor to remove alloreactive cells from the tumor microenvironment and prolong survival of banked CAR T cells. Project 3 investigators will exploit a constitutive IL7 receptor to enable T cells to sustain activation and expansion in the presence of immunosuppressive molecules and will also evaluate combination therapy with Panobinostat (4) Make T and NKT cell immunotherapy more broadly applicable by using banked normal donor cells. To make cells immediately available, we will evaluate several sources of banked cells including banked NKT cells as an “off-the-shelf” product (Project 1), knock down of αβ TCR (Project 2) and banked EBV specific T cells (Project 3). 5) Ensure transferred banked immune effectors are not rejected by the host immune system. We will enable infused immune effectors to be resistant to the host immune response by; evaluating knock down of ß2 microglobulin (B2M) to diminish MHC Class 1 expression, and of the MHC Class II invariant chain (Project 1); adding a novel alloimmune defense receptor (Project 2); or taking advantage of the ability of a CD30 CAR to target alloreactive T cells (Project 3). At the conclusion of these proposed studies, we will have evaluated the clinical activity and safety of several strategies with genetically modified immune effector cells in NHL and HL and gained insight into immune and tumor factors that correlate with clinical outcome. Successful completion of these studies should increase the potency and improve accessibility of these cellular immunotherapies for lymphoma.