Targeted genome modifications for improved adoptive T-Cell immunotherapy Laurent Poirot, Alexandre Juillerat, Julien Valton, Anne-Sophie Gautron and Philippe Duchateau CELLECTIS SA, 8 rue de la Croix Jarry, 75013 Paris, France.
Highlights •The presence of immune infiltrate in tumors has been correlated with a good prognosis following treatment.•Tumor-infiltrating lymphocytes have been utilized for the treatment of melanoma.•To broaden this therapy for other cancers, T cells have been genetically modified with either a T cell receptor or a chimeric antigen receptor.•Potential hurdles and novel strategies will be discussed for realizing the full potential of adoptive immunotherapy becoming a standard of care treatment for cancer.
REVIEW | Designing Chimeric Antigen Receptors to Effectively and Safely Target Tumors #Immunotherapy http://t.co/VdrlbuXb5w Highlights •Description of structural elements of chimeric antigen receptors used to engineer T cells.•Differences between T cell receptor and chimeric antigen receptor recognition.•Types of T cells that can be engineered to target tumor cells.•Strategies for augmenting function and selectivity of chimeric antigen receptors.•Strategies for improving safety of chimeric antigen receptor modified T cells.
AbstractAdoptive immunotherapy with T cells expressing a tumor-associated chimeric antigen receptor (CAR) provides a promising approach for tumor therapy. We designed a clinical trial for multiple myeloma (MM) treatment with CAR-modified T cells recognizing CD138 (CART-138). Five patients diagnosed with chemotherapy-refractory MM were enrolled into this trial, although one later advanced to plasma cell leukemia. By intravenous infusions, these patients received CD3+ CART-138 cells in an escalating dose. No intolerable toxicity was observed during this process. CART-138 cells were expanded to a level 1,000 times higher than the initial engraftment level and were maintained in the peripheral blood. In addition, increased CART-138 cells were also detected in the bone marrow. Four of the five patients had stable disease (SD) longer than three months, and one patient with advanced plasma cell leukemia had a reduction of the myeloma cells in her peripheral blood (from 10.5% to <3%). This study suggests that the treatment of CART-138 is safe, feasible, and tolerable and has potential antitumor activity in vivo, warranting further research in MM treatment using CART-138.
Although adoptive T-cell therapy holds promise for the treatment of many cancers, its clinical utility has been limited by problems in delivering targeted lymphocytes to tumor sites, and the cells' inefficient expansion in the immunosuppressive tumor microenvironment. Here we describe a bioactive polymer implant capable of delivering, expanding and dispersing tumor-reactive T cells. The approach can be used to treat inoperable or incompletely removed tumors by situating implants near them or at resection sites. Using a mouse breast cancer resection model, we show that the implants effectively support tumor-targeting T cells throughout resection beds and associated lymph nodes, and reduce tumor relapse compared to conventional delivery modalities. In a multifocal ovarian cancer model, we demonstrate that polymer-delivered T cells trigger regression, whereas injected tumor-reactive lymphocytes have little curative effect. Scaffold-based T-cell delivery may provide a viable treatment option for inoperable tumors and reduce the rate of metastatic relapse after surgery.
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