Luminary Inc

ΓΔ CAR T-CELLULAR VACCINE FOR SOLID CANCERS - SOLID TUMORS, SUCH AS COLORECTAL CANCER (CRC) AND LUNG ADENOCARCINOMA (LUAD), PRESENT A FORMIDABLE CHALLENGE IN CANCER TREATMENT. WHILE CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL THERAPIES HAVE ACHIEVED REMARKABLE SUCCESS IN BLOOD CANCERS, THEIR EFFECTIVENESS AGAINST SOLID TUMORS REMAINS LIMITED. CURRENT CAR T-CELL THERAPIES AND DENDRITIC-CELL (DC) VACCINES GENERALLY LACK FDA APPROVAL FOR CRC OR LUAD, AND EXISTING CLINICAL TRIALS HAVE SHOWN LIMITED SUCCESS. THE ONE APPROVED DC VACCINE FOR CRC, SIPULEUCERL-T, ONLY PROVIDES MARGINAL IMPROVEMENTS IN SURVIVAL. THE URGENCY FOR NOVEL INTERVENTIONS IS UNDERSCORED BY THE PRESSING NEED TO IMPROVE SURVIVAL RATES AND OVERCOME THE CHALLENGES POSED BY SOLID TUMORS. LUMINARY THERAPEUTICS IS DEVELOPING A FUTURISTIC APPROACH TO TARGETING SOLID CANCERS: A DUAL-ACTION ANTIGEN-PRESENTING CAR ΓΔ T-CELL (DACART) THERAPY THAT COMBINES THE STRENGTHS OF CAR T-CELL THERAPY WITH THOSE OF CANCER VACCINATION. ΓΔ T-CELLS ARE A UNIQUE SUB-TYPE OF T-CELLS THAT CAN FUNCTION BOTH AS A DIRECT CYTOTOXIC IMMUNE CELL AND AS A PROFESSIONAL ANTIGEN PRESENTING CELL AND THUS CAN BE ENGINEERED TO DIRECTLY KILL CANCER VIA A CANCER-SPECIFIC CAR LIKE A CAR T-CELL AND TO ACTIVATE A PATIENT’S OWN IMMUNE SYSTEM TO KILL CANCER BY DISPLAYING CANCER-SPECIFIC ANTIGENS ON MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) LIKE A DC VACCINE. ADDITIONALLY, ΓΔ T-CELLS REQUIRE LESS ENGINEERING TO PROVIDE SAFE ALLOGENEIC CELL THERAPY, BOAST HIGH MIGRATORY CAPABILITIES, AND CAN BE RELIABLY EXPANDED TO HIGH NUMBERS IN THE LAB. THIS STUDY WILL ENGINEER DACART CELLS USING TCBUSTER TRANSPOSON TECHNOLOGY TO PRESENT COMMON CANCER ANTIGENS TO ENDOGENOUS T CELLS IN COMBINATION WITH EXPRESSING A CAR TARGETING MESOTHELIN, A COMMON SURFACE ANTIGEN EXPRESSED IN BOTH CRC AND LUAD. IN VITRO STUDIES WILL DEMONSTRATE THE ABILITY OF DACART CELLS TO BOTH DIRECTLY KILL TUMOR CELL LINES AND TO ACTIVATE CANCER-SPECIFIC T CELLS. IN VIVO ANIMAL STUDIES WILL THEN DEMONSTRATE THE ABILITY OF DACART CELLS TO CONTROL CRC OR LUAD TUMORS THROUGH BOTH DIRECT KILLING AND ACTIVATION OF ENDOGENOUS T CELLS. FOLLOWING THESE IN VITRO AND IN VIVO EFFICACY STUDIES, THIS PROJECT WILL CONDUCT SAFETY STUDIES TO DEMONSTRATE THE SPECIFICITY OF THIS TREATMENT AND DEVELOP CLINICAL-SCALE PRODUCTION PROCESS AND SAFETY SPECIFICATIONS TO PREPARE THIS TREATMENT FOR TRANSLATION TO THE CLINIC. MATCHING THE EFFECTIVENESS OF CAR-T FOR BLOOD CANCERS BY COMBINING CYTOTOXIC CAR-T CELL THERAPY AND CANCER VACCINATION IN A SINGLE CELL THERAPY THAT EFFECTIVELY KILLS SOLID TUMORS WHILE ALSO STIMULATING AN ENDOGENOUS ANTI-TUMOR IMMUNE RESPONSE WOULD BE A BREAKTHROUGH IN THE TREATMENT OF MANY OF THE DEADLIEST CANCERS. IF THIS APPROACH IS SUCCESSFUL WITH CRC OR LUAD, THE APPROACH CAN BE APPLIED TO OTHER SOLID TUMORS, INCLUDING OTHER PREVALENT AND DEADLY CANCERS LIKE PROSTATE, AND BREAST.

ALLOGENEIC BAFF LIGAND BASED CAR T CELLS AS A NOVEL THERAPY FOR B CELL MALIGNANCIES - ABSTRACT SINCE THE FIRST FDA APPROVAL OF CHIMERIC ANTIGEN RECEPTOR (CAR) T CELL THERAPY IN 2017, THE USE OF ENGINEERED T CELLS EXPRESSING SPECIFIC CARS TO TREAT CANCER HAS GENERATED DURABLE CURES FOR MANY PATIENTS. NEVERTHELESS, A SIGNIFICANT SUBSET OF PATIENTS WITH B CELL MALIGNANCIES RELAPSE FOLLOWING TREATMENT DUE TO LACK OF CAR T CELL PERSISTENCE AND THE ABILITY OF CANCER CELLS TO CHANGE WITH TIME AND EVADE THERAPEUTIC INTERVENTIONS. AUTOLOGOUS T CELL THERAPIES ALSO CARRY SIGNIFICANT TIMELINE AND COST BURDENS, MAKING WIDESPREAD ADOPTION DIFFICULT. IN THIS APPLICATION, WE PROPOSE A NOVEL ALLOGENEIC CAR T CELL THERAPY AIMED AT IMPROVING OUTCOMES FOR PATIENTS WITH MANTLE CELL LYMPHOMA (MCL) BY OVERCOMING DEFICIENCIES PRESENT IN CURRENT GENERATION CD19 TARGETED THERAPEUTICS. B CELL ACTIVATING FACTOR (BAFF) PROVIDES CRITICAL SURVIVAL SIGNALS TO BOTH NORMAL AND NEOPLASTIC B CELLS THROUGH A FAMILY OF RECEPTORS (BAFF RECEPTOR, TACI, AND BCMA) THUS MITIGATING POTENTIAL FOR ANTIGEN ESCAPE. BAFF AND ITS RECEPTORS HAVE REMAINED UNDEREXPLORED IN THE CONTEXT OF B CELL MALIGNANCIES WHERE STRATEGIES HAVE RELIED OVERWHELMINGLY ON PAN B CELL ANTIGENS SUCH AS CD19 AND CD20. SINCE BAFF BINDS ITS RECEPTORS WITH MODERATE AFFINITY, WE BELIEVE THIS WILL INCREASE THE ABILITY OF THESE CELLS TO FORM MEMORY POPULATIONS AND ENGAGE IN SERIAL KILLING. WE WILL LEVERAGE THIS LIGAND-BASED CAR DESIGN IN AN ALLOGENEIC GAMMA DELTA (D) T CELL PLATFORM, AS D T CELLS HAVE BEEN SHOWN TO HAVE HIGH REPLICATIVE PROPERTIES IN VITRO AND DO NOT MEDIATE GRAFT VERSUS HOST DISEASE IN NEW HOSTS. WE HAVE PRODUCED PRELIMINARY DATA THAT CONFIRMS OUR ABILITY TO USE THE NON- VIRAL TCBUSTER DNA TRANSPOSON SYSTEM TO GENERATE T CELLS WITH BAFF-CAR EXPRESSION. THE OVERALL OBJECTIVE OF THIS PROPOSAL IS TO FURTHER DEVELOP AND EVALUATE OUR D BAFF-CAR T CELL THERAPY FOR THE TREATMENT OF MCL IN IND ENABLING STUDIES. IN DOING SO, OUR ALLOGENEIC BAFF-CAR T CELL THERAPY SUPPORTS AN URGENTLY NEEDED SHIFT IN THERAPEUTIC DEVELOPMENT TOWARD NEW TUMOR ANTIGENS THAT PROTECT AGAINST ANTIGEN ESCAPE WHILE REDUCING THE MANUFACTURING BURDEN ASSOCIATED WITH CELLULAR THERAPIES THROUGH USE OF A READILY AVAILABLE CELL SOURCE.

AN ALLOGENEIC GAMMA/DELTA ARMORED DUAL-TARGETING CAR WITH SPLIT COSTIMULATORY DOMAINS TO TARGET EPITHELIAL OVARIAN CARCINOMA - ABSTRACT CAR T CELL THERAPIES HAVE PRODUCED ROBUST REMISSIONS IN SEVERAL HEMATOLOGICAL MALIGNANCIES. HOWEVER, THEY HAVE NOT ACHIEVED THE SAME SUCCESS AGAINST SOLID TUMORS. THESE TREATMENTS FAIL FOR MULTIPLE REASONS, INCLUDING ANTIGEN ESCAPE AND POOR T CELL PERSISTENCE IN THE IMMUNOSUPPRESSIVE TUMOR MICROENVIRONMENT. ADDITIONALLY, MANY PATIENTS RECEIVING T CELL THERAPY EXPERIENCE SERIOUS, SOMETIMES LIFE-THREATENING SIDE EFFECTS. HERE, WE PROPOSE A CAR T PRODUCT – AN ARMORED SPLIT CAR – THAT COMBINES 2 INNOVATIVE STRATEGIES SPECIFICALLY TAILORED TO ADDRESS THE UNIQUE CHALLENGES PRESENTED BY SOLID TUMORS, AS WELL AS AN INDUCIBLE SUICIDE SWITCH TO ENHANCE SAFETY. MOREOVER, WE ARE DEVELOPING THIS PRODUCT ON OUR PROPRIETARY ALLOGENEIC ΓΔ T CELL PLATFORM. THESE CELLS DISPLAY INNATE ANTI-TUMOR PROPERTIES AND DO NOT MEDIATE GVHD. WE USE A “SPLIT CAR” APPROACH, WHEREIN TWO CAR MOLECULES, EACH TARGETING A DIFFERENT ANTIGEN, ARE EXPRESSED BY A SINGLE T CELL AND DIMERIZE UPON ANTIGEN BINDING. BY TARGETING 2 ANTIGENS, WE REDUCE THE POTENTIAL FOR ANTIGEN ESCAPE. EACH CAR MOLECULE CONTAINS EITHER A CD28 OR 4-1BB COSTIMULATORY DOMAIN WHICH ARE INDEPENDENTLY ACTIVATED TO COOPERATIVELY ENHANCE CYTOKINE RELEASE, CELL SURVIVAL, AND PROLIFERATION. THE HETERODIMERIZED CARS TRIGGER ACTIVATION THROUGH A SINGLE SHARED CD3Ζ DOMAIN INCORPORATED ON ONE OF THE CAR CHAINS. IN ADDITION, OUR ENGINEERED T CELLS EXPRESS A BINDING MOLECULE TO SEQUESTER AND DISABLE THE TUMOR-SECRETED IMMUNOSUPPRESSIVE CYTOKINE, TGFΒ. LASTLY, WE ARE INCLUDING A TEGFR SAFETY SWITCH SO THAT THE CLINICAL PRODUCT CAN BE RAPIDLY ELIMINATED IN VIVO IN CASE OF SEVERE SIDE EFFECTS. EFFICIENT GENE DELIVERY OF SUCH A LARGE CASSETTE IS MADE FEASIBLE BY USING THE TC BUSTER TRANSPOSON SYSTEM, WHICH CAN STABLY INTEGRATE TRANSGENES AS LARGE AS 10 KB WITH AN ACCEPTABLE COPY NUMBER AND A SUPERIOR SAFETY PROFILE COMPARED TO VIRAL TRANSDUCTION. TRANSPOSON-BASED GENE DELIVERY ALSO CIRCUMVENTS THE LONG MANUFACTURING TIMELINES AND BOTTLENECKS THAT BESET VIRAL METHODS. WE ARE ADAPTING THE ARMORED SPLIT CAR TO TREAT EPITHELIAL OVARIAN CARCINOMA BY TARGETING THE TUMOR ANTIGENS MESOTHELIN (MSLN) AND CHONDROITIN SULFATE PROTEOGLYCAN-4 (CSPG4). THESE ANTIGENS ARE OVEREXPRESSED IN AT LEAST 40% OF OVARIAN CANCER PATIENTS AND ARE ASSOCIATED WITH POOR OUTCOMES. WE WILL TEST OUR ARMORED SPLIT CAR IN VITRO USING A CO-CULTURE TARGET CELL KILLING ASSAY WITH OVARIAN CANCER LINES THAT ARE SINGLE- OR DOUBLE-POSITIVE FOR MSLN AND CSPG4. WE WILL TEST HOW WELL THE ENGINEERED CELLS RESIST EXHAUSTION IN A SERIAL KILLING ASSAY IN WHICH T CELLS ARE EXPOSED TO ANTIGEN IN CO- CULTURE OVER ~14 DAYS AND MULTIPLE PASSAGES, THEN ASSESSED FOR RELEVANT ACTIVATION AND EXHAUSTION MARKERS. WE WILL ALSO TEST THE TEGFR SAFETY SWITCH BY CULTURING THE CELLS WITH THE INDUCER, CETUXIMAB, AND MEASURING SELECTIVE LYSIS OF ENGINEERED CELLS. LASTLY, WE WILL ASSAY TUMOR KILLING BY THE ARMORED SPLIT CAR IN A MOUSE MODEL OF OVARIAN CANCER. THESE EXPERIMENTS ARE DESIGNED TO COLLECTIVELY DEMONSTRATE EFFICACY OF OUR PRODUCT UNDER STRESS CONDITIONS AND WILL LEAD INTO ANTICIPATED PHASE II PRECLINICAL STUDIES TO ASSESS TOXICITY AND SAFETY.

MYD88 FUSION PROTEIN WITH ANTIGEN SPECIFIC T CELL THERAPY FOR ENHANCED RESPONSE IN SOLID TUMORS

SIMULTANEOUS TARGETING OF TUMOR AND STROMA CELLS TO ENHANCE SOLID TUMOR CAR-T CELL THERAPY - ABSTRACT THE USE OF T CELLS ENGINEERED TO EXPRESS SPECIFIC CHIMERIC ANTIGEN RECEPTORS (CARS) TO TREAT CANCER HAS GENERATED DURABLE CURES FOR MANY TYPES OF CANCER AND RESULTED IN THE FIRST FDA APPROVED CAR-T CELL THERAPY TO TREAT CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IN 2017. DESPITE THIS SUCCESS, CAR-T IMMUNOTHERAPIES HAVE BEEN MUCH LESS EFFECTIVE AT TARGETING SOLID TUMORS. PART OF THIS LIMITED SUCCESS STEMS FROM THE SOLID TUMOR MICROENVIRONMENT, WHICH FORMS A PHYSICAL BARRIER TO IMMUNE CELL INFILTRATION AND PRODUCES SOLUBLE FACTORS THAT DOWNREGULATE T CELL ACTIVITY AND ACCELERATE T CELL EXHAUSTION. WHILE IMMUNOTHERAPIES TARGETING SOLID TUMORS ARE INITIALLY EFFECTIVE, THE TUMOR MICROENVIRONMENT’S INHIBITION OF T CELLS PREVENTS THESE TREATMENTS FROM PRODUCING DURABLE RESPONSES. IN THIS APPLICATION, WE PROPOSE A NOVEL CAR-T CELL THERAPY AIMED TO IMPROVE OUTCOMES FOR PATIENTS WITH ADVANCED STAGE PANCREATIC CANCER BY OVERCOMING THE DEFICIENCIES THAT PLAGUE CURRENT CAR-T CELL THERAPIES. TO THIS END, WE WILL ENGINEER T CELLS TO EXPRESS MULTIPLE CARS, ENABLING THESE CELLS TO TARGET TUMOR CELLS AND CELLS IN THE IMMUNE-SUPPRESSIVE TUMOR MICROENVIRONMENT. SPECIFICALLY, WE WILL LEVERAGE THE NON-VIRAL, TC BUSTER DNA TRANSPOSON SYSTEM TO INSERT A LARGE MULTICISTRONIC GENETIC CONSTRUCT CONTAINING MULTIPLE CARS AND A SELECTION MARKER INTO T CELLS. USING THIS PLATFORM, WE WILL GENERATE T CELLS WITH CARS TARGETING MESOTHELIN (MSLN), A PROTEIN EXPRESSED BY 80-85% OF PANCREATIC CANCER TUMORS, AND FIBROBLAST ACTIVATION PROTEIN (FAP), A MARKER OF CANCER ASSOCIATED FIBROBLASTS IN THE TUMOR MICROENVIRONMENT. WE WILL THEN SELECT A PURE POPULATION OF T CELLS EXPRESSING MSLN- AND FAP-CARS AND DETERMINE THE ACTIVITY AND SPECIFICITY OF THESE CELLS IN VITRO. WE EXPECT THAT ENGINEERED T CELLS WILL GENERATE A SPECIFIC AND ROBUST RESPONSE, ELICITING CYTOTOXIC FUNCTIONS ONLY AGAINST CELLS EXPRESSING THEIR TARGET ANTIGEN. WE WILL THEN DETERMINE THE EFFICACY OF ENGINEERED T CELLS IN VIVO USING A XENOGRAFT MOUSE MODEL TO GENERATE MSLN AND FAP POSITIVE PANCREATIC CARCINOMAS FOLLOWED BY ADOPTIVE TRANSFER OF T CELLS. WE EXPECT IMMUNOTHERAPEUTIC DELIVERY OF BISPECIFIC T CELLS EXPRESSING FAP-CARS AND MSLN- CARS WILL ELICIT A ROBUST AND LONG-LASTING T CELL RESPONSE AGAINST MSLN+/FAP+ SOLID TUMORS RESULTING IN TUMOR SHRINKAGE AND INCREASED SURVIVAL. FURTHERMORE, WE EXPECT THE DEVELOPMENT OF A FLEXIBLE, EFFICIENT, AND RELIABLE PROCESS TO GENERATE BISPECIFIC T CELLS WITH A SINGLE, NON-VIRAL GENE DELIVERY APPROACH WILL FACILITATE THE EMERGENCE OF NOVEL THERAPIES TO OVERCOME MANY ISSUES FACING ENGINEERED T CELL THERAPY TODAY, INCLUDING ANTIGEN ESCAPE AND TARGET SPECIFICITY.

ALLOGENEIC BAFF LIGAND BASED CAR T-CELLS AS A NOVEL THERAPY FOR SYSTEMIC LUPUS ERYTHEMATOUS - ABSTRACT SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A COMPLEX, CHRONIC AUTOIMMUNE DISEASE WITH NO CURE WHICH AFFECTS 1.5 MILLION AMERICANS. SLE IS A RHEUMATIC DISEASE WHICH CAN LEAD TO SEVERE ORGAN DYSFUNCTION, INCLUDING END STAGE RENAL DISEASE. AUTOREACTIVE B CELLS HAVE EMERGED AS PRIMARY DRIVERS OF THE DISEASE AND THE PRESENCE OF ANTI-NUCLEAR ANTIBODIES IS A BIOMARKER FOR DIAGNOSIS. THERAPIES TARGETING B CELLS AND THE B CELL ACTIVATING FACTOR (BAFF) SIGNALING AXIS, INCLUDING BELIMUMAB, A MONOCLONAL ANTIBODY TARGETING BAFF, HAVE SHOWN PROMISING RESULTS IN REDUCING SEVERITY OF DISEASE IN B CELL ASSOCIATED AUTOIMMUNITY, BUT THESE TREATMENTS ARE NOT CURATIVE. A RECENT STUDYING USING CD19 CHIMERIC ANTIGEN RECEPTOR (CAR) T CELL THERAPY LED TO B CELL CLEARANCE AND DISEASE REMISSION IN 4 OF 5 PATIENTS. EACH OF THESE PATIENTS WERE IN EARLY-STAGE LUPUS, BUT THE ONE WHO DID NOT RESPOND HAD THE LONGEST-TERM DISEASE AT 9 YEARS. THIS STUDY INDICATES B CELL CLEARANCE CAN RESOLVE SLE DISEASE PROGRESSION, BUT THE CD19-CAR TREATMENT WAS LIMITED IN TARGETING ALL THE AUTOREACTIVE B CELLS, INCLUDING LONG-LIVED PLASMA CELLS WHICH PRODUCE AUTOREACTIVE ANTIBODY BUT DO NOT EXPRESS CD19. WE THUS SEEK TO CIRCUMVENT THIS ISSUE IN A NEW TREATMENT FOR SLE USING AN ALLOGENEIC BAFF-LIGAND BASED CAR D T CELL PRODUCT. THE BAFF FAMILY RECEPTORS BAFFR, TACI, AND BCMA ARE HIGHLY EXPRESSED ON B CELLS AT DIFFERENT PROPORTIONS DEPENDING ON THEIR MATURATION STATE INCLUDING PLASMA CELLS. WE HYPOTHESIZE THAT ELIMINATION OF ALL AUTOREACTIVE B CELLS, INCLUDING LONG-LIVED PLASMA CELLS IN THE BONE MARROW, WILL REDUCE THE PRODUCTION OF AUTOANTIBODIES AND LEAD TO LONG TERM REMISSION. THE USE OF D T CELLS ALLOWS FOR THE MASS PRODUCTION OF ALLOGENEIC CAR T CELLS FROM A SINGLE T CELL DONOR, REDUCING COST AND INCREASING SAFETY OVERSIGHT DURING MANUFACTURING. WE HAVE PRODUCED PRELIMINARY DATA THAT CONFIRMS OUR ABILITY TO USE THE NON-VIRAL TCBUSTER DNA TRANSPOSON SYSTEM TO GENERATE D T CELLS WITH BAFF-CAR EXPRESSION AND SHOW THAT THESE CELLS ARE EFFECTIVE AT ELIMINATING CELLS EXPRESSING THE BAFF FAMILY OF RECEPTORS. TO TEST THE EFFICACY OF THE CAR IN THE CONTEXT OF SLE, WE PROPOSE TWO COMPLEMENTARY AIMS THAT WILL ASSESS THE EXPRESSION OF BAFF RECEPTORS IN SLE PATIENT B CELLS AND TEST THE ACTIVITY AND SELECTIVITY OF THESE CELLS AGAINST PATIENT B CELLS IN VITRO. FINALLY, WE WILL TEST THE EFFICACY OF THE BAFF-CAR D T CELLS IN REDUCING INFLAMMATION, RENAL DISEASE, AND AUTOANTIBODY PRODUCTION IN A HUMANIZED MOUSE MODEL OF SLE. WE HOPE TO IMPROVE OUTCOMES IN SLE BY ADVANCING THIS TECHNOLOGY TO IND-ENABLING STUDIES.

PURPOSE: TO SUPPORT AN ARTIST-IN-RESIDENCE PROGRAM FOR ARTISTS CURATORS AND CRITICS.

PURPOSE: TO SUPPORT AN ARTIST-IN-RESIDENCE PROGRAM FOR ARTISTS AND CURATORS.

PURPOSE: TO SUPPORT AN ARTIST-IN-RESIDENCE PROGRAM FOR ARTISTS CURATORS AND CRITICS.

TO SUPPORT AN ARTIST-IN-RESIDENCE PROGRAM.

TO SUPPORT AN ARTIST-IN-RESIDENCE PROGRAM.

TO SUPPORT AN INTERNATIONAL ARTIST-IN-RESIDENCE PROGRAM.

TO SUPPORT AN ARTIST-IN-RESIDENCE PROGRAM.

TO SUPPORT AN INTERNATIONAL ARTIST-IN-RESIDENCE PROGRAM.

ASSISTANCE TO FIREFIGHTERS GRANT

ASSISTANCE TO FIREFIGHTERS GRANT