Background:Targeted T-cell therapy has emerged as a promising strategy for the treatment of hematological malignancies.However,its application to solid tumors presents significant challenges due to the limited accessi...Background:Targeted T-cell therapy has emerged as a promising strategy for the treatment of hematological malignancies.However,its application to solid tumors presents significant challenges due to the limited accessibility and heterogeneity.Localized delivery of tumor-specific T-cells using biomaterials has shown promise,however,procedures required for genetic modification and generation of a sufficient number of tumor-specific T-cells ex vivo remain major obstacles due to cost and time constraints.Methods:Polyethylene glycol(PEG)-based three-dimensional(3D)scaffolds were developed and conjugated with positively charged poly-L-lysine(PLL)using carbamide chemistry for efficient loading of lentiviruses(LVs)carrying tumor antigen-specific T-cell receptors(TCRs).The physical and biological properties of the scaffold were extensively characterized.Further,the scaffold loaded with OVA-TCR LVs was implanted in B16F10 cells expressing ovalbumin(B16-OVA)tumor model to evaluate the anti-tumor response and the presence of transduced T-cells.Results:Our findings demonstrate that the scaffolds do not induce any systemic inflammation upon subcutaneous implantation and effectively recruit T-cells to the site.In B16-OVA melanoma tumor-bearing mice,the scaffolds efficiently transduce host T-cells with OVA-specific TCRs.These genetically modified T-cells exhibit homing capability towards the tumor and secondary lymphoid organs,resulting in a significant reduction of tumor size and systemic increase in anti-tumor cytokines.Immune cell profiling revealed a significantly high percentage of transduced T-cells and a notable reduction in suppressor immune cells within the tumors of mice implanted with these scaffolds.Conclusions:Our scaffold-based T-cell therapy presents an innovative in situ localized approach for programming T-cells to target solid tumors.This approach offers a viable alternative to in vitro manipulation of T-cells,circumventing the need for large-scale in vitro generation and culture of tumor-specific T-cells.It offers an off-the-shelf alternative that facilitates the use of host cells instead of allogeneic cells,thereby,overcoming a major hurdle.展开更多
India has proposed the helium-cooled solid breeder blanket concept as a tritium breeding module to be tested in ITER.The module has lithium titanate for tritium breeding and beryllium for neutron multiplication.Beryll...India has proposed the helium-cooled solid breeder blanket concept as a tritium breeding module to be tested in ITER.The module has lithium titanate for tritium breeding and beryllium for neutron multiplication.Beryllium also enhances tritium breeding.A design for the module is prepared for detailed analysis.Neutronic analysis is performed to assess the tritium breeding rate,neutron distribution,and heat distribution in the module.The tritium production distribution in submodules is evaluated to support the tritium transport analysis.The tritium breeding density in the radial direction of the module is also assessed for further optimization of the design.The heat deposition profile of the entire module is generated to support the heat removal circuit design.The estimated neutron spectrum in the radial direction also provides a more in-depth picture of the nuclear interactions inside the material zones.The total tritium produced in the HCSB module is around 13.87 mg per full day of operation of ITER,considering the 400 s ON time and 1400 s dwell time.The estimated nuclear heat load on the entire module is around 474 kW,which will be removed by the high-pressure helium cooling circuit.The heat deposition in the test blanket model(TBM)is huge(around 9 GJ)for an entire day of operation of ITER,which demonstrates the scale of power that can be produced through a fusion reactor blanket.As per the Brayton cycle,it is equivalent to 3.6 GJ of electrical energy.In terms of power production,this would be around 1655 MWh annually.The evaluation is carried out using the MCNP5 Monte Carlo radiation transport code and FEDNL 2.1 nuclear cross section data.The HCSB TBM neutronic performance demonstrates the tritium production capability and high heat deposition.展开更多
The Indian test blanket module（TBM） program in ITER is one of the major steps in the Indian fusion reactor program for carrying out the R＆D activities in the critical areas like design of tritium breeding blankets ...The Indian test blanket module（TBM） program in ITER is one of the major steps in the Indian fusion reactor program for carrying out the R＆D activities in the critical areas like design of tritium breeding blankets relevant to future Indian fusion devices（ITER relevant and DEMO）.The Indian Lead–Lithium Cooled Ceramic Breeder（LLCB） blanket concept is one of the Indian DEMO relevant TBM,to be tested in ITER as a part of the TBM program.Helium-Cooled Ceramic Breeder（HCCB） is an alternative blanket concept that consists of lithium titanate（Li_2TiO_3） as ceramic breeder（CB） material in the form of packed pebble beds and beryllium as the neutron multiplier.Specifically,attentions are given to the optimization of first wall coolant channel design and size of breeder unit module considering coolant pressure and thermal loads for the proposed Indian HCCB blanket based on ITER relevant TBM and loading conditions.These analyses will help proceeding further in designing blankets for loads relevant to the future fusion device.展开更多
基金Department of Biotechnology(DBT,Govt of India)(BT/PR31315/MED/32/667/2019)DBT along with Wadhwani Research Center for Bioengineering,IIT Bombay(BT/INF/22/SP23026/2017)Department of Biotechnology(DBT,Govt of India)(BT/INF/22/SP17358/2016).
文摘Background:Targeted T-cell therapy has emerged as a promising strategy for the treatment of hematological malignancies.However,its application to solid tumors presents significant challenges due to the limited accessibility and heterogeneity.Localized delivery of tumor-specific T-cells using biomaterials has shown promise,however,procedures required for genetic modification and generation of a sufficient number of tumor-specific T-cells ex vivo remain major obstacles due to cost and time constraints.Methods:Polyethylene glycol(PEG)-based three-dimensional(3D)scaffolds were developed and conjugated with positively charged poly-L-lysine(PLL)using carbamide chemistry for efficient loading of lentiviruses(LVs)carrying tumor antigen-specific T-cell receptors(TCRs).The physical and biological properties of the scaffold were extensively characterized.Further,the scaffold loaded with OVA-TCR LVs was implanted in B16F10 cells expressing ovalbumin(B16-OVA)tumor model to evaluate the anti-tumor response and the presence of transduced T-cells.Results:Our findings demonstrate that the scaffolds do not induce any systemic inflammation upon subcutaneous implantation and effectively recruit T-cells to the site.In B16-OVA melanoma tumor-bearing mice,the scaffolds efficiently transduce host T-cells with OVA-specific TCRs.These genetically modified T-cells exhibit homing capability towards the tumor and secondary lymphoid organs,resulting in a significant reduction of tumor size and systemic increase in anti-tumor cytokines.Immune cell profiling revealed a significantly high percentage of transduced T-cells and a notable reduction in suppressor immune cells within the tumors of mice implanted with these scaffolds.Conclusions:Our scaffold-based T-cell therapy presents an innovative in situ localized approach for programming T-cells to target solid tumors.This approach offers a viable alternative to in vitro manipulation of T-cells,circumventing the need for large-scale in vitro generation and culture of tumor-specific T-cells.It offers an off-the-shelf alternative that facilitates the use of host cells instead of allogeneic cells,thereby,overcoming a major hurdle.
文摘India has proposed the helium-cooled solid breeder blanket concept as a tritium breeding module to be tested in ITER.The module has lithium titanate for tritium breeding and beryllium for neutron multiplication.Beryllium also enhances tritium breeding.A design for the module is prepared for detailed analysis.Neutronic analysis is performed to assess the tritium breeding rate,neutron distribution,and heat distribution in the module.The tritium production distribution in submodules is evaluated to support the tritium transport analysis.The tritium breeding density in the radial direction of the module is also assessed for further optimization of the design.The heat deposition profile of the entire module is generated to support the heat removal circuit design.The estimated neutron spectrum in the radial direction also provides a more in-depth picture of the nuclear interactions inside the material zones.The total tritium produced in the HCSB module is around 13.87 mg per full day of operation of ITER,considering the 400 s ON time and 1400 s dwell time.The estimated nuclear heat load on the entire module is around 474 kW,which will be removed by the high-pressure helium cooling circuit.The heat deposition in the test blanket model(TBM)is huge(around 9 GJ)for an entire day of operation of ITER,which demonstrates the scale of power that can be produced through a fusion reactor blanket.As per the Brayton cycle,it is equivalent to 3.6 GJ of electrical energy.In terms of power production,this would be around 1655 MWh annually.The evaluation is carried out using the MCNP5 Monte Carlo radiation transport code and FEDNL 2.1 nuclear cross section data.The HCSB TBM neutronic performance demonstrates the tritium production capability and high heat deposition.
文摘The Indian test blanket module（TBM） program in ITER is one of the major steps in the Indian fusion reactor program for carrying out the R＆D activities in the critical areas like design of tritium breeding blankets relevant to future Indian fusion devices（ITER relevant and DEMO）.The Indian Lead–Lithium Cooled Ceramic Breeder（LLCB） blanket concept is one of the Indian DEMO relevant TBM,to be tested in ITER as a part of the TBM program.Helium-Cooled Ceramic Breeder（HCCB） is an alternative blanket concept that consists of lithium titanate（Li_2TiO_3） as ceramic breeder（CB） material in the form of packed pebble beds and beryllium as the neutron multiplier.Specifically,attentions are given to the optimization of first wall coolant channel design and size of breeder unit module considering coolant pressure and thermal loads for the proposed Indian HCCB blanket based on ITER relevant TBM and loading conditions.These analyses will help proceeding further in designing blankets for loads relevant to the future fusion device.
