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DEVELOPMENT OF A NOVEL IMMUNOTHERAPEUTIC FOR ACUTE MYELOID LEUKEMIA - ACUTE MYELOID LEUKEMIA (AML) AND THE NEED FOR ADVANCED TREATMENT: AML IS A PREVALENT HEMATOLOGICAL MALIGNANCY IN ADULTS, WITH A 5-YEAR SURVIVAL RATE OF ONLY 32%. WHILE APPROXIMATELY 32,000 AML PATIENTS ARE DIAGNOSED ANNUALLY IN THE US TODAY, PROJECTIONS SUGGEST THIS WILL RISE TO 36,000 BY 2027. CURRENT TREATMENTS, SUCH AS ALLOGENEIC BONE MARROW TRANSPLANTATION, HAVE LIMITED APPLICABILITY DUE TO HIGH MORBIDITY AND TREATMENT- ASSOCIATED MORTALITY. THE PROBLEM OF IMMUNE EVASION: AML CELLS EMPLOY IMMUNE EVASION TACTICS, NOTABLY UP-REGULATION OF CO- INHIBITORY LIGANDS LIKE VASOACTIVE INTESTINAL PEPTIDE (VIP), WHICH RESULTS IN EXHAUSTED AND NON-FUNCTIONAL T CELLS, THWARTING AN EFFECTIVE ANTI-CANCER RESPONSE. CURRENT IMMUNE CHECK-POINT THERAPIES USING ANTI-PD1 AND ANTI-PD- L1 ANTIBODIES ARE INEFFECTIVE IN AML PATIENTS. SOLUTION - DEVELOPMENT OF ANT308-FC3 FUSION: CAMBIUM ONCOLOGY IS A BIOTECH START-UP DEVELOPING NOVEL IMMUNOTHERAPEUTIC DRUGS TO TREAT CANCER. CAMBIUM ONCOLOGY’S RESEARCH INDICATES THAT ROUGHLY 30% OF AML CELLS OVER-EXPRESS VIP, WHICH DAMPENS T-CELL ACTIVATION. CAMBIUM ONCOLOGY HAS A WORLDWIDE EXCLUSIVE LICENSE TO PATENTS COVERING VIP-RECEPTOR ANTAGONISTS FROM EMORY UNIVERSITY. A PEPTIDE-BASED VIP-RECEPTOR ANTAGONIST, VIPHYB, SHOWED PROMISE IN PRE-CLINICAL STUDIES BUT HAD A LIMITED POTENCY AND A SHORT HALF-LIFE. CAMBIUM ONCOLOGY USED IN SILICO SCREENS AND IN VIVO TESTING TO IDENTIFY A NOVEL VIP-RECEPTOR ANTAGONIST, ANT308, WHICH, WHEN FUSED TO THE FC REGION OF THE IGG PROTEIN, BECAME ANT308-FC3 FUSION, CAMBIUM ONCOLOGY’S LEAD CANDIDATE DRUG. ANT308-FC3 FUSION EXHIBITS ENHANCED POTENCY AGAINST PRE-CLINICAL MOUSE MODELS OF AML WITH BOTH HIGH AND LOW LEVELS OF VIP EXPRESSION. THE WORK'S FUTURE IMPACT IS INCREASED BY APPLYING THIS APPROACH TO OTHER CANCERS. SBIR PHASE 1 & 2 OBJECTIVES: PHASE 1 WILL DETERMINE ANT308-FC3 FUSION'S POTENCY IN HUMAN T CELL ACTIVATION (AIM 1), ITS ANTI-LEUKEMIA ACTIVITY IN MICE (AIM 2), AND ITS STABILITY AND PHARMACOKINETICS (AIM 3). PHASE 2 WILL FOCUS ON IN VIVO TOXICOLOGY (AIMS 4 & 5) AND PHARMACODYNAMIC STUDIES TO IDENTIFY RESPONSIVE BIOMARKERS FOR CLINICAL TRIALS (AIM 6). THE SBIR FAST-TRACK PROPOSAL AIMS TO DEVELOP AN IND PACKAGE TO SUBMIT TO THE FDA SUPPORTING A PHASE 1 CLINICAL TRIAL OF ANT308-FC3 FUSION IN AML. THE SBIR TEAM IS EXPERIENCED IN ANTI-CANCER IMMUNOLOGY AND DRUG DEVELOPMENT AND IS LED BY DR. GARY ALTMAN, PH.D., A BUSINESS EXECUTIVE WITH EXPERIENCE IN BIOTECH START-UPS AND OBTAINING FDA APPROVAL FOR IND PHARMACEUTICALS. THE PROPOSED PROJECT AIMS TO ADVANCE ANT308-FC3 FUSION AS A FIRST-IN-CLASS IMMUNOTHERAPY TO ENHANCE TREATMENT OUTCOMES FOR AML PATIENTS.

DEVELOPMENT OF A NOVEL IMMUNOTHERAPEUTIC FOR ACUTE MYELOID LEUKEMIA - ACUTE MYELOID LEUKEMIA (AML) AND THE NEED FOR ADVANCED TREATMENT: AML IS A PREVALENT HEMATOLOGICAL MALIGNANCY IN ADULTS, WITH A 5-YEAR SURVIVAL RATE OF ONLY 32%. WHILE APPROXIMATELY 32,000 AML PATIENTS ARE DIAGNOSED ANNUALLY IN THE US TODAY, PROJECTIONS SUGGEST THIS WILL RISE TO 36,000 BY 2027. CURRENT TREATMENTS, SUCH AS ALLOGENEIC BONE MARROW TRANSPLANTATION, HAVE LIMITED APPLICABILITY DUE TO HIGH MORBIDITY AND TREATMENT- ASSOCIATED MORTALITY. THE PROBLEM OF IMMUNE EVASION: AML CELLS EMPLOY IMMUNE EVASION TACTICS, NOTABLY UP-REGULATION OF CO- INHIBITORY LIGANDS LIKE VASOACTIVE INTESTINAL PEPTIDE (VIP), WHICH RESULTS IN EXHAUSTED AND NON-FUNCTIONAL T CELLS, THWARTING AN EFFECTIVE ANTI-CANCER RESPONSE. CURRENT IMMUNE CHECK-POINT THERAPIES USING ANTI-PD1 AND ANTI-PD- L1 ANTIBODIES ARE INEFFECTIVE IN AML PATIENTS. SOLUTION - DEVELOPMENT OF ANT308-FC3 FUSION: CAMBIUM ONCOLOGY IS A BIOTECH START-UP DEVELOPING NOVEL IMMUNOTHERAPEUTIC DRUGS TO TREAT CANCER. CAMBIUM ONCOLOGY’S RESEARCH INDICATES THAT ROUGHLY 30% OF AML CELLS OVER-EXPRESS VIP, WHICH DAMPENS T-CELL ACTIVATION. CAMBIUM ONCOLOGY HAS A WORLDWIDE EXCLUSIVE LICENSE TO PATENTS COVERING VIP-RECEPTOR ANTAGONISTS FROM EMORY UNIVERSITY. A PEPTIDE-BASED VIP-RECEPTOR ANTAGONIST, VIPHYB, SHOWED PROMISE IN PRE-CLINICAL STUDIES BUT HAD A LIMITED POTENCY AND A SHORT HALF-LIFE. CAMBIUM ONCOLOGY USED IN SILICO SCREENS AND IN VIVO TESTING TO IDENTIFY A NOVEL VIP-RECEPTOR ANTAGONIST, ANT308, WHICH, WHEN FUSED TO THE FC REGION OF THE IGG PROTEIN, BECAME ANT308-FC3 FUSION, CAMBIUM ONCOLOGY’S LEAD CANDIDATE DRUG. ANT308-FC3 FUSION EXHIBITS ENHANCED POTENCY AGAINST PRE-CLINICAL MOUSE MODELS OF AML WITH BOTH HIGH AND LOW LEVELS OF VIP EXPRESSION. THE WORK'S FUTURE IMPACT IS INCREASED BY APPLYING THIS APPROACH TO OTHER CANCERS. SBIR PHASE 1 & 2 OBJECTIVES: PHASE 1 WILL DETERMINE ANT308-FC3 FUSION'S POTENCY IN HUMAN T CELL ACTIVATION (AIM 1), ITS ANTI-LEUKEMIA ACTIVITY IN MICE (AIM 2), AND ITS STABILITY AND PHARMACOKINETICS (AIM 3). PHASE 2 WILL FOCUS ON IN VIVO TOXICOLOGY (AIMS 4 & 5) AND PHARMACODYNAMIC STUDIES TO IDENTIFY RESPONSIVE BIOMARKERS FOR CLINICAL TRIALS (AIM 6). THE SBIR FAST-TRACK PROPOSAL AIMS TO DEVELOP AN IND PACKAGE TO SUBMIT TO THE FDA SUPPORTING A PHASE 1 CLINICAL TRIAL OF ANT308-FC3 FUSION IN AML. THE SBIR TEAM IS EXPERIENCED IN ANTI-CANCER IMMUNOLOGY AND DRUG DEVELOPMENT AND IS LED BY DR. GARY ALTMAN, PH.D., A BUSINESS EXECUTIVE WITH EXPERIENCE IN BIOTECH START-UPS AND OBTAINING FDA APPROVAL FOR IND PHARMACEUTICALS. THE PROPOSED PROJECT AIMS TO ADVANCE ANT308-FC3 FUSION AS A FIRST-IN-CLASS IMMUNOTHERAPY TO ENHANCE TREATMENT OUTCOMES FOR AML PATIENTS.

DEVELOPMENT OF A NOVEL ARMORED CAR-T IMMUNOTHERAPEUTIC FOR PANCREATIC CANCER - PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) REPRESENTS A MAJOR CHALLENGE IN ONCOLOGY, THE THIRD LEADING CAUSE OF CANCER-RELATED DEATH, AND A 5-YEAR SURVIVAL RATE OF ONLY 11%. THE DENSE, IMMUNOSUPPRESSIVE TUMOR MICROENVIRONMENT (TME) OF PDAC SIGNIFICANTLY HINDERS THE EFFICACY OF CURRENT THERAPEUTIC STRATEGIES, INCLUDING THE INNOVATIVE CAR T CELL THERAPIES THAT HAVE SHOWN PROMISE IN HEMATOLOGIC MALIGNANCIES. A SIGNIFICANT CONTRIBUTOR TO THIS IMMUNOSUPPRESSION IS THE SECRETION OF VASOACTIVE INTESTINAL PEPTIDE (VIP) WITHIN THE PDAC TME BY CANCER CELLS AND IMMUNE CELLS THAT LIMITS THE EFFICACY OF ADOPTIVE T CELL THERAPIES. ADDRESSING THIS URGENT NEED, CAMBIUM ONCOLOGY PROPOSES A NOVEL APPROACH TO ENHANCE CAR T CELL THERAPY'S POTENCY AGAINST PDAC BY COUNTERING THE IMMUNOSUPPRESSIVE EFFECTS OF VIP PREVALENT IN PDAC TUMORS. OUR PIONEERING STRATEGY INVOLVES ENGINEERING CAR T CELLS THAT TARGET THE EXTRACELLULAR DOMAIN OF MUC16 (MUC16CD), A MARKER ABUNDANT IN PDAC TUMORS AND STROMA, TO SECRETE AN OPTIMIZED FORM OF THE VIP RECEPTOR (VIPR) ANTAGONIST, ANT308FC. PRELIMINARY FINDINGS INDICATE THAT CAR T CELLS ENDOWED WITH THE CAPABILITY TO SECRETE VIPR ANTAGONISTS DEMONSTRATE ENHANCED METABOLIC FLEXIBILITY, A PREDOMINANCE OF MEMORY T CELL SUBSETS, AND SUPERIOR ANTI-TUMOR ACTIVITY. THIS PROJECT IS STRUCTURED TO VALIDATE THE ANT308-FC FUSION AS A SECRETED AGENT FROM CAR T CELLS TO DISRUPT THE VIP-MEDIATED IMMUNOSUPPRESSION WITHIN THE PDAC TME, THEREBY ENHANCING T CELL FUNCTIONALITY AND PERSISTENCE, REMODELING THE PDAC TME, AND FACILITATING THE ERADICATION OF PDAC CELLS. THE PROPOSED “FAST-TRACK” SBIR RESEARCH AND DEVELOP PLAN IS DIVIDED INTO TWO PHASES: PHASE 1 AIMS TO DEVELOP AND VALIDATE ANT308FC FOR SECRETION BY CAR T CELLS (AIM 1) AND TO IDENTIFY THE FORM OF VIPR ANTAGONISM THAT EXHIBITS THE MOST POTENT ANTI-TUMOR EFFECTS IN PDAC MODELS (AIM 2). A GO/NO- GO DECISION BASED ON THE IN VIVO EFFICACY OF ANT308 VARIANTS WILL DETERMINE THE PROGRESSION TO PHASE 2. PHASE 2 IS FOCUSED ON EVALUATING THE TOXICITY AND BIODISTRIBUTION (AIM 3), AND MECHANISM OF ACTION OF THE SELECTED CAR/VIPRA T CELLS (AIM 4), ALONGSIDE PREPARING FOR IND SUBMISSION (AIM 5). OUR AIMS ARE ROOTED IN SOLID PRELIMINARY DATA AND LEVERAGE A CLINICALLY VALIDATED CAR TARGET (MUC16CD), POSITIONING THIS WORK AT THE FOREFRONT OF TRANSLATIONAL RESEARCH FOR PDAC. THIS PROJECT STANDS TO SIGNIFICANTLY IMPACT THE TREATMENT LANDSCAPE FOR PDAC BY PROVIDING A NOVEL, EFFICACIOUS THERAPY OPTION. THE SUCCESSFUL DEVELOPMENT AND CLINICAL TRANSLATION OF CAR/VIPRA T CELLS COULD NOT ONLY REVOLUTIONIZE PDAC TREATMENT BUT ALSO SERVE AS A PLATFORM TECHNOLOGY APPLICABLE TO A BROAD RANGE OF CANCERS, UNDERSCORING THE POTENTIAL OF CAR T CELL THERAPIES IN SOLID TUMORS. IMPACT: CAMBIUM ONCOLOGY'S ENDEAVOR INTO COMMERCIALIZATION OF CAR T CELLS THAT SECRETE A VIP RECEPTOR ANTAGONIST IS ALIGNED WITH THE COMPANY’S CORE COMPETENCY IN DEVELOPING NOVEL IMMUNE-ONCOLOGY DRUGS AND ADDRESSES THE PRESSING NEED FOR INNOVATIVE, EFFECTIVE TREATMENTS FOR PDAC. RESULTS FROM THE PROPOSED SBIR CAN DRAMATICALLY IMPROVE PATIENT OUTCOMES IN THIS HIGH-MORTALITY CANCER.

DEVELOPMENT OF A NOVEL IMMUNOTHERAPEUTIC FOR ACUTE MYELOID LEUKEMIA - ACUTE MYELOID LEUKEMIA (AML) AND THE NEED FOR ADVANCED TREATMENT: AML IS A PREVALENT HEMATOLOGICAL MALIGNANCY IN ADULTS, WITH A 5-YEAR SURVIVAL RATE OF ONLY 32%. WHILE APPROXIMATELY 32,000 AML PATIENTS ARE DIAGNOSED ANNUALLY IN THE US TODAY, PROJECTIONS SUGGEST THIS WILL RISE TO 36,000 BY 2027. CURRENT TREATMENTS, SUCH AS ALLOGENEIC BONE MARROW TRANSPLANTATION, HAVE LIMITED APPLICABILITY DUE TO HIGH MORBIDITY AND TREATMENT- ASSOCIATED MORTALITY. THE PROBLEM OF IMMUNE EVASION: AML CELLS EMPLOY IMMUNE EVASION TACTICS, NOTABLY UP-REGULATION OF CO- INHIBITORY LIGANDS LIKE VASOACTIVE INTESTINAL PEPTIDE (VIP), WHICH RESULTS IN EXHAUSTED AND NON-FUNCTIONAL T CELLS, THWARTING AN EFFECTIVE ANTI-CANCER RESPONSE. CURRENT IMMUNE CHECK-POINT THERAPIES USING ANTI-PD1 AND ANTI-PD- L1 ANTIBODIES ARE INEFFECTIVE IN AML PATIENTS. SOLUTION - DEVELOPMENT OF ANT308-FC3 FUSION: CAMBIUM ONCOLOGY IS A BIOTECH START-UP DEVELOPING NOVEL IMMUNOTHERAPEUTIC DRUGS TO TREAT CANCER. CAMBIUM ONCOLOGY’S RESEARCH INDICATES THAT ROUGHLY 30% OF AML CELLS OVER-EXPRESS VIP, WHICH DAMPENS T-CELL ACTIVATION. CAMBIUM ONCOLOGY HAS A WORLDWIDE EXCLUSIVE LICENSE TO PATENTS COVERING VIP-RECEPTOR ANTAGONISTS FROM EMORY UNIVERSITY. A PEPTIDE-BASED VIP-RECEPTOR ANTAGONIST, VIPHYB, SHOWED PROMISE IN PRE-CLINICAL STUDIES BUT HAD A LIMITED POTENCY AND A SHORT HALF-LIFE. CAMBIUM ONCOLOGY USED IN SILICO SCREENS AND IN VIVO TESTING TO IDENTIFY A NOVEL VIP-RECEPTOR ANTAGONIST, ANT308, WHICH, WHEN FUSED TO THE FC REGION OF THE IGG PROTEIN, BECAME ANT308-FC3 FUSION, CAMBIUM ONCOLOGY’S LEAD CANDIDATE DRUG. ANT308-FC3 FUSION EXHIBITS ENHANCED POTENCY AGAINST PRE-CLINICAL MOUSE MODELS OF AML WITH BOTH HIGH AND LOW LEVELS OF VIP EXPRESSION. THE WORK'S FUTURE IMPACT IS INCREASED BY APPLYING THIS APPROACH TO OTHER CANCERS. SBIR PHASE 1 & 2 OBJECTIVES: PHASE 1 WILL DETERMINE ANT308-FC3 FUSION'S POTENCY IN HUMAN T CELL ACTIVATION (AIM 1), ITS ANTI-LEUKEMIA ACTIVITY IN MICE (AIM 2), AND ITS STABILITY AND PHARMACOKINETICS (AIM 3). PHASE 2 WILL FOCUS ON IN VIVO TOXICOLOGY (AIMS 4 & 5) AND PHARMACODYNAMIC STUDIES TO IDENTIFY RESPONSIVE BIOMARKERS FOR CLINICAL TRIALS (AIM 6). THE SBIR FAST-TRACK PROPOSAL AIMS TO DEVELOP AN IND PACKAGE TO SUBMIT TO THE FDA SUPPORTING A PHASE 1 CLINICAL TRIAL OF ANT308-FC3 FUSION IN AML. THE SBIR TEAM IS EXPERIENCED IN ANTI-CANCER IMMUNOLOGY AND DRUG DEVELOPMENT AND IS LED BY DR. GARY ALTMAN, PH.D., A BUSINESS EXECUTIVE WITH EXPERIENCE IN BIOTECH START-UPS AND OBTAINING FDA APPROVAL FOR IND PHARMACEUTICALS. THE PROPOSED PROJECT AIMS TO ADVANCE ANT308-FC3 FUSION AS A FIRST-IN-CLASS IMMUNOTHERAPY TO ENHANCE TREATMENT OUTCOMES FOR AML PATIENTS.