Immunothérapie | EPFL Graph Search

vignette|Thérapie adoptive par lymphocytes T (non annotée). Les lymphocytes T spécifiques du cancer peuvent être obtenus par fragmentation et isolement des lymphocytes infiltrant la tumeur, ou par génie génétique des cellules du sang périphérique. Les cellules sont activées L' consiste à administrer des substances stimulant les défenses immunitaires du malade pour lutter contre des pathologies installées, le plus souvent des cancers, voire contre des maladies dégénératives. Ceci inclut les thérapies utilisant des protéines (anticorps) produites par les cellules du système immunitaire, en particulier les immunoglobulines, sans que l'objectif de cette thérapie ne soit nécessairement la stimulation de l'immunité. On distingue l'immunothérapie locale (rare) et l'immunothérapie générale (beaucoup plus fréquente). mise au point par Leonard Noon et John Freeman en 1911. Les essais modernes d'immunothérapie remontent aux années 1970, basés sur des anticorps polyclonaux. Depuis, d'autres mol

Mechanical Immunoengineering of T Cells for Enhanced Cancer Immunotherapy

Kewen Lei

Cancer is one of the leading causes of death globally. Immunotherapy represents one of the most promising cancer treatments inducing complete and durable responses in a fraction of cancer patients. Despite the unprecedented clinical success achieved by T cell-based cancer immunotherapies, there are tremendous outstanding challenges, including low response rate and severe toxicities, which substantially limit the clinical benefits in a majority of cancer patients. At present, enormous efforts have been spent on modulating biochemical interactions for improving the efficacy and safety of T cell-based cancer immunotherapy. Besides biochemical exchanges, mechanical interactions are universal in every step of T cell immunity and are crucial in regulating T cell functions. Thus, immunoengineering approaches that modulate mechanical interactions in T cell immunity hold great promise to improve current cancer immunotherapy. This thesis aims to develop novel mechanical immunoengineering approaches for improving cancer immunotherapy. Specifically, it includes the following parts:Developing a spiky artificial antigen-presenting cell (aAPC) to enhance ex vivo T cell expansion. Ex vivo expansion of T cells is critical in adoptive T cell therapy (ACT) to ensure an effective therapeutic dosage for cancer treatment. By mimicking the dendritic morphology of dendritic cells, I developed a spiky TiO2 microparticle presenting T cell stimulatory ligands as an aAPC to enhance ex vivo T cell expansion. The spiky aAPC outperformed the smooth counterpart, as well as Dynabead®, a standard aAPC used in clinical manufacturing of ACT therapy, for T cell activation and expansion depending on F-actin polymerization in T cells. Therefore, this finding identifies the morphology of aAPCs as a critical parameter to improve ex vivo T cell manufacturing for ACT therapy.Boosting T cell-mediated cytotoxicity by stiffening cancer cells. I discovered that cancer cell softening derived from cholesterol enrichment in the plasma membrane led to resistance to T cell-mediated cytotoxicity. Stiffening cancer cells via membrane cholesterol depletion substantially enhanced T cell-mediated cytotoxicity against cancer cells through augmenting T cell mechanical force but not any known biochemical pathways of T cell-mediated cytotoxicity. Cancer cell stiffening intervention in vivo enhanced the efficacy of ACT therapy in multiple preclinical solid tumor models. Cancer cell softness thus represents a new immune checkpoint of mechanical basis, and therapeutically targeting this mechanical immune checkpoint has the potential to improve the clinical response of T cell-based cancer immunotherapy.Utilizing T cell force as a trigger to achieve specific release of anti-cancer drugs. Specific delivery of T cell supporting drugs and/or anti-cancer drugs into tumors has the potential to increase the response rate of ACT therapy without causing systemic toxicity. To this end, I developed a T cell force-responsive drug release system based on a mesoporous silica microparticle with DNA force sensors as gatekeepers. T cell force as a highly specific signal upon recognizing cancer cells presenting cognate antigens was shown to trigger specific drug release when T cell receptor signaling was activated. Further, the T cell force-responsive drug release system could deliver anti-cancer drugs in vitro and in vivo in a T cell force-dependent manner and holds promise to enhance cancer immunotherapy.

EPFL2022

Targeting and Modulating Tumor-Associated Sites with Novel Nanoparticle-Based Immunotherapies

Laura Jeanbart

Cancer is a global disease and a leading cause of death worldwide. While surgery, radiotherapy and chemotherapy comprise the classical tools to eradicate tumors, they do not cure cancer, cannot prevent metastases, lead to side effects, and most importantly they do not instruct the patientʼs immune system to recognize and fight tumor cells. Since the discovery of the immune systemʼs implication in cancer, immunotherapies, which aim at using and educating the immune system to fight and reject cancer, have come to complement classical tumor-debulking methods. A major goal of immunotherapy is to induce or activate effector cytotoxic CD8+ T lymphocytes that can infiltrate and kill the tumor while overcoming immune suppressive mechanisms, which impede their efficacy. Moreover, cancer immunotherapies aim at inducing memory to tumor antigens to prevent relapse or metastases, which traditional therapies cannot do. Dendritic cell (DC) targeting and activation are key for inducing adaptive immunity. Our laboratory has developed synthetic nanoparticles (NPs) capable of draining through lymphatics to target skin-draining lymph nodes (LNs) and being phagocytosed by resident antigen-presenting cells (APCs) upon intradermal injection. We developed a reproducible method to conjugate tumor antigens to NPs and co-delivered them with CpG-conjugated NPs. We found that a NP vaccine composed of a single melanoma-derived peptide (TRP- 2180-188) led to dramatic tumor growth delay in melanoma and was more efficient than a NP vaccine containing several tumor antigens from whole tumor cell lysate (TL). These findings contradicted our hypothesis that immunization with TL might lead to a broader T cell response and hence improved therapeutic outcomes. Additionally, we found that the dose of CpG could modulate the magnitude of the therapeutic outcomes in both single epitope and multiple antigen based NP-vaccines. Considering the efficacy of the developed NP vaccines, we used them as a tool to ask a fundamental and extremely relevant question regarding the influence of vaccine administration site on clinical efficacy: is it therapeutically more beneficial to target a tumor- draining lymph node (tdLN), which is immune suppressed but tumor antigen-primed, or a non-tdLN, which is neither suppressed nor primed by the tumor? We found that targeting the tdLN with NP vaccines led to significantly enhanced therapeutic outcomes in two different tumor models over targeting a non-tdLN, and that efficacy relied on NP conjugation of antigen and adjuvant. This suggested that antigen drainage from the tumor might be available to APCs in the tdLN and we further hypothesized that therapies that lead to immunogenic tumor cell death might synergize with a tdLN-targeted adjuvant approach. While cytotoxic modalities, such as chemotherapy and radiotherapy, have traditionally been used for their ability to kill tumor cells, tumor cells shed antigens and debris upon cell death that drain to the tdLN. Consistent with our hypothesis, targeting an adjuvant to the tdLN enhanced therapeutic benefits of chemo- and radio- therapy, while targeting a non-tdLN did not. We hypothesized that targeting the tdLN with NP vaccines might switch the tdLN microenvironment from a suppressive to an immunogenic one. This suggested that direct targeting of active suppressive mechanisms in the tumor might further improve immunotherapy. We thus engineered a nano-sized micellar carrier loaded with 6-thioguanine (MC-6TG), a cytotoxic drug used in leukemia, and explored its use in targeting T cell- impairing myeloid-derived suppressor cells (MDSCs) in order to enhance the efficacy of therapeutic vaccines. MC-6TG entirely eradicated both Ly6c+ monocytic and Ly6g+ granulocytic MDSCs for up to 7 d in the blood, tumor and tdLN of tumor-bearing mice. Since MC-6TG also targeted certain subsets of macrophages and DCs, depleting MDSCs did not have an impact on the efficacy of a NP vaccine, which relies on APCs for efficacy. However, MC-6TG synergized with adoptively transferred CD8+ T cells, significantly delaying tumor growth and enhancing survival in a murine model of implantable melanoma. Overall, this thesis describes the design and implementation of a novel approach to immunotherapy: we engineered NP-based therapeutic vaccines, optimized their delivery route to enhance efficacy, and simultaneously tackled immune suppressive cells in the tumor microenvironment to allow optimal therapeutic outcomes. The technologies and methods developed in this work are particularly relevant to clinical oncology and have the potential to benefit cancer patients by improving cancer therapy efficacy.

EPFL2013

New roles of the lymphatic endothelium in modulating adaptive immunity: implications for immune tolerance and cancer immunotherapy

Lambert Charles François Potin

Lymphatic vessels have traditionally been considered as passive conduits for interstitial fluid drainage and for immune cell trafficking to lymph nodes. In the last two decades, many studies have challenged this classical dogma: lymphatic endothelial cells (LECs) were shown to actively interact with immune cells by secreting chemokines and cytokines, and presenting antigens to T cells. These newly described functions pinpoint a multi-faceted role of LECs in orchestrating the immune response through both passive and active mechanisms. Yet, precise mechanisms leading to antigen-specific fine-tuning of the T cell response remain unexplored. Moreover, although lymphatics have been shown to play important roles in cancer, the contributions of LECs in regulating antitumor immunity have been largely overlooked by the biomedical community. This doctoral thesis aimed at filling these gaps. First, in order to investigate the mechanisms and implications of LEC antigen presentation to CD4+ T cells, we engineered a mouse model where LECs lacked the ability to present antigens to CD4+ T cells. In these mice, antigen-specific responses to vaccination were increased when compared to wild-type controls. Moreover, we demonstrated that LECs were poor inducers of CD4+ T cell activation in vitro, and that they could dampen CD4+ T cell activation by dendritic cells. Taken together, these findings suggest that LECs participate to the peripheral immune tolerance of CD4+ T cells. Second, we investigated the immunological consequences of the development of lymphatic vessels, called lymphangiogenesis, in mouse melanoma. Upon induction of tumor lymphangiogenesis, we observed striking tumor enrichment with immune cells, which resulted in a higher sensitivity of those tumors to immunotherapy. We subsequently demonstrated that inducing lymphangiogenesis in a mouse model of cold tumors, which lack immune infiltrates and do not respond to immunotherapies, could restore their responsiveness to immunotherapy treatments. Third, to predict which cancer types were the most likely to replicate the findings we obtained in mouse melanoma, we mined The Cancer Genome Atlas database for gene expression. We identified a set of cancers, such as colon adenocarcinoma and cholangiocarcinoma, where high expression of the lymphangiogenic growth factor was associated with a strong T cell signature. This doctoral thesis unveiled new immunomodulatory functions of LECs by which antigen-specific immune tolerance is induced. Additionally, it opened new avenues to target lymphatics therapeutically in cancer to potentiate immunotherapies. We believe this work contributes to demonstrating the immunological importance of LECs, and hope that lymphatics will be considered as an important immunomodulatory player of the tumor microenvironment when developing novel immunotherapies.

EPFL2018