2024
627 EVEREST-2: a seamless phase 1/2 study of A2B694, a logic-gated Tmod CAR T-cell therapy, in patients with mesothelin-expressing solid tumors with human leukocyte antigen-A*02 loss of heterozygosity
Molina J, Hazim A, Dorigo O, Punekar S, Avila M, Simeone D, Kirtane K, Konecny G, Ward J, Block M, Specht J, Boyd L, Lou Y, Park J, Xuan J, Eskander R, Ong G, Davila M, Langeberg W, Maus M, Mardiros A, Locke F, Wise A, Maloney D, Welch J, Randolph Hecht J. 627 EVEREST-2: a seamless phase 1/2 study of A2B694, a logic-gated Tmod CAR T-cell therapy, in patients with mesothelin-expressing solid tumors with human leukocyte antigen-A*02 loss of heterozygosity. 2024, a721-a722. DOI: 10.1136/jitc-2024-sitc2024.0627.Peer-Reviewed Original Research662 A phase1 study of autologous engineered CD4+ and CD8+ T cells, HLA-A*11:01-restricted, KRAS G12V-specific, transgenic TCR; CD8α/β coreceptor and a FAS41BB switch receptor in patients with solid tumors
Mitchell S, Khan B, Payumo F, Gabriela Chiorean E, Gahvari Z, Randolph Hecht J, Hurwitz M, Leidner R, Lenz H, Pelster M, Schoenfeld A, Punekar S, Zhao D, Basu S, Nagorsen D. 662 A phase1 study of autologous engineered CD4+ and CD8+ T cells, HLA-A*11:01-restricted, KRAS G12V-specific, transgenic TCR; CD8α/β coreceptor and a FAS41BB switch receptor in patients with solid tumors. 2024, a759-a759. DOI: 10.1136/jitc-2024-sitc2024.0662.Peer-Reviewed Original Research1 Oral: First Clinical Results from A Phase 1 Trial of PRT3789, a First-in-Class Intravenous SMARCA2 Degrader, in Patients with Advanced Solid Tumors with a SMARCA4 Mutation
Yap T, Dowlati A, Dagogo-Jack I, Vibert J, Spira A, Garcia V, Punekar S, Calvo E, Sonpavde G, Awad M, Riess J, Hernández-Guerrero T, Herzberg B, Italiano A, Swalduz A, LoRusso P, Smit E, Garon E, Novotny W, Guo R. 1 Oral: First Clinical Results from A Phase 1 Trial of PRT3789, a First-in-Class Intravenous SMARCA2 Degrader, in Patients with Advanced Solid Tumors with a SMARCA4 Mutation. European Journal Of Cancer 2024, 211: 114530. DOI: 10.1016/j.ejca.2024.114530.Peer-Reviewed Original Research603O First clinical results from a phase I trial of PRT3789: A first-in-class intravenous SMARCA2 degrader, in patients with advanced solid tumors with a SMARCA4 mutation
Guo R, Dowlati A, Dagogo-Jack I, Vibert J, Spira A, Garcia V, Punekar S, Calvo E, Sonpavde G, Awad M, Riess J, Guerrero T, Herzberg B, Italiano A, Swalduz A, Lorusso P, Smit E, Garon E, Novotny W, Yap T. 603O First clinical results from a phase I trial of PRT3789: A first-in-class intravenous SMARCA2 degrader, in patients with advanced solid tumors with a SMARCA4 mutation. Annals Of Oncology 2024, 35: s483-s484. DOI: 10.1016/j.annonc.2024.08.670.Peer-Reviewed Original ResearchAFNT-211: A phase 1 study of autologous CD4+ and CD8+ T cells engineered to express a high avidity HLA-A*11:01-restricted, KRAS G12V-specific, transgenic TCR, a CD8α/β coreceptor, and a FAS41BB switch receptor in patients with advanced/metastatic solid tumors.
Mitchell S, Khan B, Payumo F, Chiorean E, Gahvari Z, Hecht J, Hurwitz M, Leidner R, Lenz H, Pelster M, Punekar S, Schoenfeld A, Zhao D, Vallaster M, Nagorsen D. AFNT-211: A phase 1 study of autologous CD4+ and CD8+ T cells engineered to express a high avidity HLA-A*11:01-restricted, KRAS G12V-specific, transgenic TCR, a CD8α/β coreceptor, and a FAS41BB switch receptor in patients with advanced/metastatic solid tumors. Journal Of Clinical Oncology 2024, 42: tps8650-tps8650. DOI: 10.1200/jco.2024.42.16_suppl.tps8650.Peer-Reviewed Original ResearchOptimal biological doseCD8+ T cellsAutologous CD4+Advanced/metastatic solid tumorsT cellsSolid tumorsSwitch receptorsDose expansionDose escalationCD4+Transgenic TCRMechanism of actionDose-limiting toxicity observation periodRecommended phase 2 doseT cell cytotoxic activityIncreased T cell activationCD4+ T cellsHelper T cell responsesPreventing T cell exhaustionPost-treatment follow-up periodChimeric switch receptorsPhase 2 doseImmunosuppressive tumor microenvironmentT cell exhaustionDuration of responseEVEREST-1: A seamless phase 1/2 study of A2B530, a carcinoembryonic antigen (CEA) logic-gated Tmod CAR T-cell therapy, in patients with solid tumors associated with CEA expression also exhibiting human leukocyte antigen (HLA)-A*02 loss of heterozygosity (LOH).
Molina J, Simeone D, Smith C, Welling T, Kirtane K, Grierson P, Morelli M, Hecht J, Patel S, Locke F, Weng W, Fakih M, Vong J, Liechty K, Ng E, Welch J, Maus M, Maloney D, Go W, Punekar S. EVEREST-1: A seamless phase 1/2 study of A2B530, a carcinoembryonic antigen (CEA) logic-gated Tmod CAR T-cell therapy, in patients with solid tumors associated with CEA expression also exhibiting human leukocyte antigen (HLA)-A*02 loss of heterozygosity (LOH). Journal Of Clinical Oncology 2024, 42: tps2698-tps2698. DOI: 10.1200/jco.2024.42.16_suppl.tps2698.Peer-Reviewed Original ResearchOff-tumor toxicityT-cell therapyCAR-T cell therapyChimeric antigen receptorHLA-A*02T cellsCarcinoembryonic antigenHLA LOHNormal cellsCEA expressionSolid tumorsRecommended phase 2 doseLack of tumor-specific targetsNon-small cell lungDose-escalation portionPhase 2 doseDose-expansion phaseT-cell engagersObjective of Phase 1Tumor-specific targetingTreating solid tumorsT cell receptorOn-targetBayesian optimal interval designCheckpoint inhibitorsAn open-label, phase 1, multicenter study to evaluate the safety and preliminary anti-tumor activity of NT-112 in human leukocyte antigen-C*08:02–positive adult patients with unresectable, advanced, and/or metastatic solid tumors that are positive for the KRAS G12D mutation.
Punekar S, Pelster M, Becerra C, Hecht J, Paulson A, Grierson P, Morelli M, Leidner R, Kamgar M, Baranda J, Kazmi S, Shergill A, Robinson A, Patel A, Yan Y, van Heijst J, Demars N, Perez A, Cohen S, Fakih M. An open-label, phase 1, multicenter study to evaluate the safety and preliminary anti-tumor activity of NT-112 in human leukocyte antigen-C*08:02–positive adult patients with unresectable, advanced, and/or metastatic solid tumors that are positive for the KRAS G12D mutation. Journal Of Clinical Oncology 2024, 42: tps2677-tps2677. DOI: 10.1200/jco.2024.42.16_suppl.tps2677.Peer-Reviewed Original ResearchT cell receptor-engineered T cellsPancreatic ductal adenocarcinomaKRAS G12D mutationG12D mutationT cellsHLA-C*08:02Open-labelSolid tumorsDriver mutationsTCR-T cell therapyLandscape of cancer treatmentPreliminary anti-tumor activityPotential anti-tumor activityRECIST v1.1 criteriaDose-limiting toxicityTargetable driver mutationsDose-escalation studyCD8 T cellsMetastatic solid tumorsOncogenic driver mutationsAscending dose levelsSolid tumor malignanciesLimited treatment optionsFDA-approved therapiesRecombinant IL-2EVEREST-2: A seamless phase 1/2 study of A2B694, a mesothelin (MSLN) logic-gated Tmod CAR T-cell therapy, in patients with solid tumors that show MSLN expression and human leukocyte antigen (HLA)-A*02 loss of heterozygosity (LOH).
Punekar S, Hecht J, Smith C, Simeone D, Dorigo O, Boyd L, Kirtane K, Ward J, Locke F, Morelli M, Block M, Eskander R, Langeberg W, Liechty K, Ong G, Go W, Maloney D, Maus M, Welch J, Molina J. EVEREST-2: A seamless phase 1/2 study of A2B694, a mesothelin (MSLN) logic-gated Tmod CAR T-cell therapy, in patients with solid tumors that show MSLN expression and human leukocyte antigen (HLA)-A*02 loss of heterozygosity (LOH). Journal Of Clinical Oncology 2024, 42: tps2699-tps2699. DOI: 10.1200/jco.2024.42.16_suppl.tps2699.Peer-Reviewed Original ResearchChimeric antigen receptorOff-tumor toxicityT-cell therapyCAR-T cell therapyMesothelin expressionT cellsHLA-A*02Solid tumorsNormal cellsChimeric antigen receptor T cellsRecommended phase 2 doseCAR T cell activityLack of tumor-specific targetsNon-small cell lung cancerCryopreserved T cellsMajor body cavitiesPhase 2 doseDose-expansion phaseObjective of Phase 1Tumor-specific targetingCell lung cancerSolid tumor typesFirst-in-humanT cell activationOn-target
2023
634 EVEREST-1: A seamless phase 1/2 study of CEA logic-gated Tmod CAR T-cell therapy (A2B530) in patients with solid tumors associated with CEA expression also exhibiting HLA loss of heterozygosity (LOH)
Punekar S, Welling T, Randolph Hecht J, Molina J, Smith C, Garon E, Pia Morelli M, Fakih M, Kirtane K, Grierson P, Patel S, Lin Y, Kopetz S, Locke F, Ward J, Lozac’hmeur A, Frigault M, Nikiforow S, Weng W, Specht J, Dragovich T, Vong J, Mardiros A, Liechty K, Go W, Welch J, Ng E, Maus M, Maloney D, Simeone D. 634 EVEREST-1: A seamless phase 1/2 study of CEA logic-gated Tmod CAR T-cell therapy (A2B530) in patients with solid tumors associated with CEA expression also exhibiting HLA loss of heterozygosity (LOH). 2023, a724-a725. DOI: 10.1136/jitc-2023-sitc2023.0634.Peer-Reviewed Original Research
2022
The current state of the art and future trends in RAS-targeted cancer therapies
Punekar S, Velcheti V, Neel B, Wong K. The current state of the art and future trends in RAS-targeted cancer therapies. Nature Reviews Clinical Oncology 2022, 19: 637-655. PMID: 36028717, PMCID: PMC9412785, DOI: 10.1038/s41571-022-00671-9.Peer-Reviewed Original ResearchConceptsDuration of responseNovel combination therapiesCombination therapyClinical trialsTherapeutic strategiesSolid tumorsMutant KRASTumor microenvironmentDrug resistanceRAS pathwayCancer cellsDevelopment of inhibitorsCancer therapyOncogenic RASPatientsOncogenic proteinsTherapyKRASResistance mechanismsMutant isoformsInhibitorsRASMalignancyTumorsCancer