Over the last two decades,lymphoma idiotype vaccines have been the first human cancer vaccines to show striking evidence of biological and clinical efficacy on the one hand,as well as clinical benefit on the other.Mor...Over the last two decades,lymphoma idiotype vaccines have been the first human cancer vaccines to show striking evidence of biological and clinical efficacy on the one hand,as well as clinical benefit on the other.More recently,however,three large-scale,independent,randomized clinical trials on idiotypic vaccination have failed to achieve their main clinical endpoints for reasons likely to depend more on flaws in each clinical trial’s study design than on each vaccination strategy per se.Independently of these considerations,a major hurdle for the development of this substantially innocuous and yet potentially very effective type of treatment has been the fact that,even to date,no factors ascertainable before vaccination have been prospectively singled out as predictors of subsequently vaccine-induced,idiotypespecific immune as well as clinical responses.The aim of this review article is precisely to analyze what has been and what could be done in this respect in order to give a greater chance of success to future trials aimed at regulatory approval of idiotype vaccines.展开更多
AIM: To assess whether the addition of a customized, active immunotherapy to standard of care including fluorescence-guided surgery, may provide hints of an improved survival for patients with poor-prognosis, incurabl...AIM: To assess whether the addition of a customized, active immunotherapy to standard of care including fluorescence-guided surgery, may provide hints of an improved survival for patients with poor-prognosis, incurable glioblastoma multiform. METHODS: Preliminary to our ongoing, phase-Ⅱ clinical trial, we conducted a small pilot study enrolling five consecutive patients with resectable glioblastoma. In terms of Recursive Partitioning Analysis, four patientswere class Ⅴ and one was class Ⅳ. In all five cases, fluorescence-guided surgery was employed, followed by rapid steroid discontinuation. Patients were then treated with a combination of standard radio-chemotherapy with temozolomide and tumor lysate-pulsed, mature dendritic cell-based vaccinations.RESULTS: Though all five patients ultimately progressed, with any further treatment left to the sole decision of the treating oncologist, active immunotherapy was very well tolerated and induced specific immune responses in all three patients for whom enough material was available for such an assessment. Median progression-free survival was 16.1 mo. Even more important, median and mean overall survival were 27 mo and 26 mo, respectively. Three patients have died with an overall survival of 9 mo, 27 mo and 27.4 mo, while the other two are still alive at 32 mo and 36 mo, the former receiving treatment with bevacizumab, while the latter has now been off therapy for 12 mo. Four of five patients were alive at two years.CONCLUSION: Active immunotherapy with tumor lysate-pulsed, autologous dendritic cells is feasible, safe, well tolerated and biologically efficacious. A phase-Ⅱ study is ongoing to possibly improve further on our very encouraging clinical results.展开更多
The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer(TNBC),primarily by contributing to tumor cell survival and treatment resistance.However,the pre...The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer(TNBC),primarily by contributing to tumor cell survival and treatment resistance.However,the precise mechanisms remain unclear.In a model of local recurrence(LR),circulating tumor cells(CTC)engrafting in the post-resection tumor bed developed a radioresistant phenotype linked to an ENPP1+-gene signature which was also identified in TNBC patients,suggesting ENPP1´s role in genome integrity.Blockade of ENPP1 using a permeable ENPP1 inhibitor(AVA-NP-695)reduced radioresistance,mechanistically attributed to decreased homologous recombination(HR)resulting in persistent DNA damage,as evidenced by enhanced tail moment and sustainedγH2AX formation.This impaired DNA damage repair(DDR)sensitized tumor cells to ionizing radiation(IR).Notably,several DDR inhibitors(i)(including PARPi and ATMi)showed the highest synergy score in a targeted pharmacological screening.In vivo,dual ENPP1/ATM inhibition heightened radiosensitivity,compromised tumor cell survival and enhanced STINGTBK1 signaling by preventing ENPP1-mediated cGAMP hydrolysis.This resulted in robust innate and long-lasting adaptive antitumor immune memory responses,leading to significant tumor regression.Remarkably,combined treatment post-IR reduced spontaneous metastasis and local recurrence,and induced abscopal effects that impacted distant tumor spread in orthotopic tumor models.Thus,these findings position ENPP1 as a critical link between genome integrity and immunosuppression,offering promising translational opportunities for treating local or distant dissemination in TNBC.展开更多
文摘Over the last two decades,lymphoma idiotype vaccines have been the first human cancer vaccines to show striking evidence of biological and clinical efficacy on the one hand,as well as clinical benefit on the other.More recently,however,three large-scale,independent,randomized clinical trials on idiotypic vaccination have failed to achieve their main clinical endpoints for reasons likely to depend more on flaws in each clinical trial’s study design than on each vaccination strategy per se.Independently of these considerations,a major hurdle for the development of this substantially innocuous and yet potentially very effective type of treatment has been the fact that,even to date,no factors ascertainable before vaccination have been prospectively singled out as predictors of subsequently vaccine-induced,idiotypespecific immune as well as clinical responses.The aim of this review article is precisely to analyze what has been and what could be done in this respect in order to give a greater chance of success to future trials aimed at regulatory approval of idiotype vaccines.
基金Supported by Spanish Health Ministry Grant MCI EC08/00186
文摘AIM: To assess whether the addition of a customized, active immunotherapy to standard of care including fluorescence-guided surgery, may provide hints of an improved survival for patients with poor-prognosis, incurable glioblastoma multiform. METHODS: Preliminary to our ongoing, phase-Ⅱ clinical trial, we conducted a small pilot study enrolling five consecutive patients with resectable glioblastoma. In terms of Recursive Partitioning Analysis, four patientswere class Ⅴ and one was class Ⅳ. In all five cases, fluorescence-guided surgery was employed, followed by rapid steroid discontinuation. Patients were then treated with a combination of standard radio-chemotherapy with temozolomide and tumor lysate-pulsed, mature dendritic cell-based vaccinations.RESULTS: Though all five patients ultimately progressed, with any further treatment left to the sole decision of the treating oncologist, active immunotherapy was very well tolerated and induced specific immune responses in all three patients for whom enough material was available for such an assessment. Median progression-free survival was 16.1 mo. Even more important, median and mean overall survival were 27 mo and 26 mo, respectively. Three patients have died with an overall survival of 9 mo, 27 mo and 27.4 mo, while the other two are still alive at 32 mo and 36 mo, the former receiving treatment with bevacizumab, while the latter has now been off therapy for 12 mo. Four of five patients were alive at two years.CONCLUSION: Active immunotherapy with tumor lysate-pulsed, autologous dendritic cells is feasible, safe, well tolerated and biologically efficacious. A phase-Ⅱ study is ongoing to possibly improve further on our very encouraging clinical results.
基金supported the Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional“Una manera de hacer Europa”to RMM(PI 19/01884 and PI22/01506)by the Government of Navarra(34/2021)/50%FEDER 2014-2020 and by the Foundation AECC(PRYES211377MART)+7 种基金funded by Cancer Research Thematic Network of the Instituto de Salud Carlos III(RTICC RD12/0036/0066)SAF2015-71606R,RTI2018-094507B-100 financed by MCIN/AEI/10.13039/501100011033/and by FEDER“Una manera de hacer Europa”MICIU PID2021-1226380B-100 and PID2024-156335OB-100supported by FIS(PI22/01253)supported by the Foundation for Applied Medical Research(FIMA)and CIBERONC(CB16/12/00443)funded by the Government of Navarra of the I+D 2022-25,GEMA(GRANATE:Grupo de Radioterapia Avanzada de Navarra,0011-1411-2022-000066 and 0011-1411-2022-000073)supported by a Project PID2023-152755OB-I00 funded by MICIU/AEI/10.13039/501100011033 and by FEDER,EU.K.Vsupported by an Investigator grant from AECC.F.L.and S.V.report research funding from Roche.F.L.and R.M.-M.report consulting fees from Ellipses Life.No potential conflicts of interest were disclosed by the other authors.
文摘The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer(TNBC),primarily by contributing to tumor cell survival and treatment resistance.However,the precise mechanisms remain unclear.In a model of local recurrence(LR),circulating tumor cells(CTC)engrafting in the post-resection tumor bed developed a radioresistant phenotype linked to an ENPP1+-gene signature which was also identified in TNBC patients,suggesting ENPP1´s role in genome integrity.Blockade of ENPP1 using a permeable ENPP1 inhibitor(AVA-NP-695)reduced radioresistance,mechanistically attributed to decreased homologous recombination(HR)resulting in persistent DNA damage,as evidenced by enhanced tail moment and sustainedγH2AX formation.This impaired DNA damage repair(DDR)sensitized tumor cells to ionizing radiation(IR).Notably,several DDR inhibitors(i)(including PARPi and ATMi)showed the highest synergy score in a targeted pharmacological screening.In vivo,dual ENPP1/ATM inhibition heightened radiosensitivity,compromised tumor cell survival and enhanced STINGTBK1 signaling by preventing ENPP1-mediated cGAMP hydrolysis.This resulted in robust innate and long-lasting adaptive antitumor immune memory responses,leading to significant tumor regression.Remarkably,combined treatment post-IR reduced spontaneous metastasis and local recurrence,and induced abscopal effects that impacted distant tumor spread in orthotopic tumor models.Thus,these findings position ENPP1 as a critical link between genome integrity and immunosuppression,offering promising translational opportunities for treating local or distant dissemination in TNBC.
