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This volume presents the most complicated and powerful cancer biotherapies developed. It provides an overview of human immune system function and the mechanisms by which adoptive cellular immunotherapies (ACI) harnesses the activity. The volume provides a vision on the developments in ACI.
This volume presents the most complicated and powerful cancer biotherapies developed. It provides an overview of human immune system function and the mechanisms by which adoptive cellular immunotherapies (ACI) harnesses the activity. The volume provides a vision on the developments in ACI.
This volume illustrates the salient aspects of cancer biology relevant to the successful implementation of immunotherapy. Topics include enhancement of antigen-specific immune responses by anti-cancer vaccines, modulation of the function of T cells within the tumor microenvironment, and the effects of genetic, epigenetic, developmental, and environmental determinants on T cell function. Other topics covered include the ex vivo expansion of T or other immune cells and their genetic modification or reprogramming to increase their ability to survive and expand when adoptively transferred back to the patients. Specific attention is devoted to the genetic manipulation of T cells through the introduction of re-directed T cell receptors, chimeric antibody receptors, and other genetic manipulation aimed at improving their effectiveness as anti-cancer agents. Furthermore, the revolutionary role of checkpoint inhibitors and their potential in combination with other immunotherapeutic approaches or with standard chemo and radiation therapy are extensively discussed.
Cancer research has progressed enormously in recent years. This review volume will address recent findings in the area of T-cell therapy for cancer, including use of tumour infiltrating lymphocytes (TILs) as a therapy for melanoma, choice of target antigens, advances in engineered receptors, methods of gene transfer to T cells, review of cell processing methods and clinical trial design. Written by leadings scientists in the field, this up-to-date review on cancer research will be an important reference source to the researchers and healthcare professionals in the field.
Adoptive cellular immunotherapy of cancer, particularly chimeric antigen receptor-transduced T cell (CAR-T) therapies, have enjoyed an explosion of clinical trials and translational and basic research in the past decade. The concept and design of the CAR, though originally intended to optimize targeting of innate natural killer cells (NK cells) to tumor-specific antigens, was laterally applied in the past decade to conventional autologous and later third-party allogeneic T cells with first-in-kind successes in leukemia immunotherapy in both adults and children. This approach also spawned the development of an entire industry focused on cancer immunotherapy, laying the foundation for the current paradigm shifts away from toxic chemo/radiotherapy to immune targeting. Aside from cytokine-release toxicities, specific obstacles plaguing existing CAR-T cell therapies include suboptimal killing by fatigued or senescent autologous patient-derived T cells derived, acquisition of tumor resistance to T-cell based immune therapies, and graft-versus-host disease (GVHD) associated with allogeneic conventional T cell therapies.
Adoptive Cell Transfer, Volume 370 in the International Review of Cell and Molecular Biology series highlights advances in the field, with this new volume presenting interesting chapters written by an international board of authors who expound on topics such as the Impact of tumor microenvironment on Adoptive Cell Transfer activity, Dendritic Cell Transfer, CAR-T Cell dysfunction and exhaustion, NK Cell-based cancer immunotherapy, Enabling CAR-T cells for solid tumors: rage against the suppressive tumor microenvironment, Improving Adoptive T-Cell therapy with cytokines administration, and What will (and should) be improved in Immunotherapy with CAR? Publishes only invited review articles on selected topics Authored by established and active cell and molecular biologists and drawn from international sources Offers a wide range of perspectives on specific subjects
Adoptive cell therapy for cancer using tumor antigen-reactive cytotoxic lymphocytes or with tumor infiltrating lymphocytes has been shown to be a potent therapy for metastatic cancer. The generation of tumor-reactive T cells is not always possible in all of the patients. To overcome this limitation, investigators can now insert highly avid T-cell receptors (TCR) into T cells that can recognize tumor antigens. Genetic engineering of TCR genes into normal T cells is a powerful new strategy to generate large numbers of defined antigen-specific cells for therapeutic application. This approach has evolved beyond experimental stage into a clinical reality. The feasibility of TCR engineered T cells has been shown to be an effective clinical strategy resulting in the regression of established tumors in recent clinical trials. In this chapter, the progress and prospects of TCR engineered T cells as a therapeutic strategy for treating patients with cancer are discussed.
Cancer treatments that are based on the reactivation, expansion, or mobilisation of the immune system, such as adoptive cellular therapies and immune-checkpoint blockade, have achieved long-lasting anti-tumour responses in cancer patients. However, there is still a high proportion of patients that do not benefit from these treatments. This highlights the need for more effective therapies. Based on the notion that adoptive cell therapies do work and are likely limited in vivo by the activation of immune modulatory pathways, this project focused on ablating negative regulation and increasing the intra-tumoural effector activity of tumour-reactive T cells. Specifically, my project aimed to genetically modify tumour infiltrating T cells by knocking-out the expression of immune- checkpoints on their surface so as to render them resistant to checkpoint inhibition, thus generating potent and long-lasting anti-tumour immunity. For this purpose, the CRISPR/Cas9 technology was used to genome edit tumour-reactive T cells using primary human tumour-infiltrating lymphocytes (TILs) obtained from melanoma and non-small-cell lung carcinoma (NSCLC) patients. The project initially focused on the generation of PD1-deficient tumour- reactive T cells as a proof of concept, as targeting this pathway with antibodies has shown clear efficacy in the clinic. Following the generation of PD1-deficient gene edited T cells, we developed LAG3-deficient and TIGIT-deficient tumour-reactive T cells, as well as T cells that were deficient for both PD1 and LAG3 expression. In sum, the overall purpose of this project was to utilise cutting edge gene editing tools to engineer tumour-reactive lymphocytes and render them resistant to checkpoint inhibition. The results from this work have established a clinically relevant pipeline for the generation of potent adoptive cell therapy products for the treatment of cancer.