MSGID: 1:317/3 63e71a02   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    CAR-T cell cancer immunotherapy gets personal    
    Fine-tuning stimulation doses to deficiencies in patient-specific CAR-   
   T cells, using artificial antigen-presenting scaffolds, enables manufacturing   
   of more potent CAR-T cell products    
      
     Date:   
         February 10, 2023   
     Source:   
         Wyss Institute for Biologically Inspired Engineering at Harvard   
     Summary:   
         Scientists have demonstrated that personalizing CAR-T cell   
         stimulation during manufacturing can significantly enhance the   
         consistency and potency of the resulting CAR-T cell products. By   
         using artificial antigen-presenting cell mimicking scaffolds   
         (APC-ms), the team was able to fine-tune the levels of T cell   
         stimulation to match the phenotype of T cells obtained from   
         leukemia patients, and significantly enhanced their ex vivo and   
         in vivo tumor-clearing abilities.   
      
      
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   FULL STORY   
   ==========================================================================   
   New adoptive T cell therapies -- in which T cells, the immune system's   
   natural hunters patrolling the body for foreign adversaries, are retrieved   
   from cancer- riddled patients, super-charged and amplified outside the   
   body, and then infused back into the same patient -- are changing the   
   prospects of cancer patients. Since 2017, when CAR (chimeric antigen   
   receptor)-T cells were green- lighted as the first modified therapeutic   
   cells by the Federal Drug Administration (FDA) to treat leukemia, five   
   similar products have since been approved and more than 20,000 people   
   have been treated with this game-changing immunotherapy.   
      
      
   ==========================================================================   
   CAR-T cells are engineered to carry synthetic membrane-spanning receptor   
   molecules that use their outside-facing portion to bind to antigens on   
   cancer cells, which their inside-facing portion responds to by switching   
   on a powerful tumor cell-destroying program. However, not all patients   
   respond equally well to CAR-T cell therapies, and cancer immunologists   
   have been trying to figure out what makes them work well or fail. Despite   
   a budding understanding of differences between cancer patients' T cells   
   and healthy individuals' T cells, these insights have not been taken   
   into account in CAR-T cell manufacturing processes. All processes use   
   a similar type of stimulation with T-cell specific agonists and general   
   immune-stimulating cytokines to create infusible CAR- T cell products,   
   irrespective of variations in the original T cells' phenotype.   
      
   Now, a collaboration between bioengineers at the Wyss Institute for   
   Biologically Inspired Engineering at Harvard University and Harvard   
   John A.   
      
   Paulson School of Engineering and Applied Sciences (SEAS) led by David   
   Mooney, Ph.D. and cancer-immunologists at the Dana-Farber Cancer   
   Institute (DFCI) led by Catherine Wu, M.D., Ph.D. has demonstrated   
   that personalizing CAR-T cell stimulation during manufacturing can   
   significantly enhance the consistency and potency of the resulting   
   CAR-T cell products. By using artificial antigen- presenting cell   
   mimicking scaffolds (APC-ms), the team was able to fine-tune the levels   
   of T cell stimulation to match the phenotype of T cells obtained from   
   leukemia patients, and significantly enhanced their ex vivo and in   
   vivo tumor-clearing abilities. The findings are published in Nature   
   Communications.   
      
   "We show that CAR-T cell products made from T cells derived from cancer   
   patients are generally less functional than CAR-T cells products   
   derived from healthy individuals," said Founding Wyss Core Faculty   
   member Mooney. "Matching the CAR-T cell antigen-stimulation dose to   
   the phenotype of patients' T cells using a precisely controllable   
   biomaterials approach that closely mimics natural antigen presentation   
   can significantly improve their function. This approach could further   
   personalize CAR-T cell therapy and remove an existing inadequacy from   
   current T cell manufacturing." Mooney also is Robert P. Pinkas Family   
   Professor of Bioengineering at SEAS, and a lead of the NIH-funded   
   Immunomaterials to Improve Immunotherapy (i3) Center coordinated at the   
   Wyss Institute. This project was conceived at the Center, and Wu is one   
   of its Principal Investigators.   
      
   Cutting the keys for personalized CAR-T therapies The team investigated   
   the phenotypes of T cells that they isolated from samples obtained from   
   patients suffering from acute lymphoblastic leukemia (ALL) and chronic   
   lymphoblastic leukemia (CLL), as well as from healthy donors. Next, they   
   utilized APC-ms to provide the T cells with different doses of anti-CD3/   
   anti-CD28 antigen stimulation and thus created a CAR-T cell library. All   
   CAR- T cell products contained in the library were then probed again for   
   functional differences, including their ability to kill cancer cells in   
   vitro. The researchers directly compared their approach with one that   
   is commonly used in CAR-T cell manufacturing, which presents the same   
   antigens on rigid magnetic beads (Dynabeads) to T cells.   
      
   A key finding was that cancer patients' T cells were much more   
   easily over- stimulated at antigen doses commonly used during CAR-T   
   cell manufacturing than "healthy" T cells. This made them lose their   
   functionality, or become more "exhausted" as immunologists say, and   
   decreased their ability to proliferate.   
      
   CAR-T cells not only need to be transformed into a functional state   
   but also amplified by millions to be able to eliminate tumor cells and   
   metastasis in the entire body.   
      
   "By exploring a precise, narrow range of stimulation doses made possible   
   with APC-ms, we show that there is something like a personalized   
   'sweet spot' for patient-derived T cells that maximizes functionality   
   and amplification, which is, on average, lower than the usual doses,"   
   said first-author David Zhang, who is a graduate student on Mooney's   
   team. "The APC-ms approach functions much more naturally than Dynabeads,   
   because highly controllable levels of T-cell signals are embedded into   
   a lipid bilayer, which allows the CAR-T cells to push and pull at them   
   as just as T cells usually do across the 'immunological synapse' between   
   them and antigen-presenting cells when T cell stimulation is at its best."   
   From in vitro studies to cell manufacturing While the team did not observe   
   any significant differences between CAR-T cells created from ALL and CLL   
   patient samples, overall their approach generated more cells with high   
   cytotoxic potential toward tumor cells, a more balanced ratio between   
   cytotoxic CD8+ T cells and CD4+ T cells that support their function,   
   and more memory T cells that themselves are not cytotoxic but can be   
   activated in later responses. In a mouse in vivo study, infused CAR-T   
   cell products created with different levels of stimulation also exhibited   
   significantly different abilities to control CD19-expressing Burkitt's   
   lymphoma, with cells again stimulated at lower than usual levels during   
   manufacturing showing the strongest potential.   
      
   "We constructed a proof-of-concept model that is based on the quantifiable   
   relationship between the phenotype of a T cell blood sample and its   
   CAR-T cell products, and that outputs an optimal T cell stimulation dose   
   for personalized CAR-T cell production," said Wu. "Given that T cell   
   samples are always fingerprinted for important markers at the beginning   
   of the cell manufacturing process, similar strategies could be devised   
   to further personalize the therapy using the APC-ms approach." Wu is   
   the Lavine Family Chair, Preventative Cancer Therapies at DFCI, and   
   Professor of Medicine at Harvard Medical School.   
      
   "Dave Mooney's team in the Wyss' Immunomaterials platform is pushing   
   the envelope of CAR-T cell and other immunotherapies using entirely   
   new engineering and materials-based approaches. Hopefully, this   
   will eventually enable us to also mobilize the immune system against   
   recalcitrant solid tumors for which no therapies exist yet. It's also   
   a great example of where less is more," said Wyss Founding Director   
   Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of   
   Vascular Biology at HMS and Boston Children's Hospital, and Hansjo"rg   
   Wyss Professor of Bioinspired Engineering at the Harvard John A.   
      
   Paulson School of Engineering and Applied Sciences.   
      
   Additional authors on the study are Wyss and SEAS researchers Kwasi   
   Adu- Berchie, Siddharth Iyer, Yutong Liu, and Joshua Brockman; DFCI   
   researcher Nicoletta Cieri, and Donna Neuberg, Sc.D., a data scientist   
   at the DFCI and member of the i3 Center. The study was funded by the   
   Wyss Institute at Harvard University, the Food and Drug Administration   
   (under award #5R01FD006589), the National Cancer Institute of the NIH   
   (under award #U54CA244726), as well as a fellowship from the Canadian   
   Institutes of Health Research.   
      
       * RELATED_TOPICS   
             o Health_&_Medicine   
                   # Stem_Cells # Lymphoma # Immune_System # Lung_Cancer #   
                   Brain_Tumor # Cancer # Leukemia # Skin_Cancer   
       * RELATED_TERMS   
             o Natural_killer_cell o Gene_therapy o   
             Monoclonal_antibody_therapy o Adult_stem_cell o Cell_(biology)   
             o Somatic_cell_nuclear_transfer o Somatic_cell o Stem_cell   
      
   ==========================================================================   
   Story Source: Materials provided   
   by Wyss_Institute_for_Biologically_Inspired_Engineering_at   
   Harvard. Original written by Benjamin Boettner. Note: Content may be   
   edited for style and length.   
      
      
   ==========================================================================   
   Journal Reference:   
      1. David K. Y. Zhang, Kwasi Adu-Berchie, Siddharth Iyer, Yutong Liu,   
         Nicoletta Cieri, Joshua M. Brockman, Donna Neuberg, Catherine   
         J. Wu, David J. Mooney. Enhancing CAR-T cell functionality in a   
         patient-specific manner. Nature Communications, 2023; 14 (1) DOI:   
         10.1038/s41467-023- 36126-7   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2023/02/230210145803.htm   
      
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