Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2008. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted.

<p>Glioblastoma (GBM) is a grade IV astrocytoma in which the median overall survival is approximately 15 months at time of diagnosis. Even with the current multi- modal therapeutic approach of surgery, chemotherapy with the DNA alkylating agent temozolomide, and radiation therapy, GBM remains uniformly lethal. Immunotherapeutic interventions are a burgeoning field in many different cancer treatments. They offer the exquisite specificity endowed by the immune system with minimal toxicities and new methods are being developed to enhance the endogenous immune responses.</p><p>With the recent identification of human cytomegalovirus (CMV) present within glioblastoma tissue but void in the surrounding normal healthy parenchyma there have been significant efforts aimed at understanding the biologic implications of the presence of the virus within GBM tissues with preliminary work demonstrating several capabilities of the virus to enhance the oncogenic process. </p><p>Likewise, a key area of importance in the development and design of effective immunotherapeutic platforms is the identification and targeting of tumor-specific antigens. The success of any immunotherapy platform relies heavily on the ability to selectively target antigens present within tumors but absent on healthy tissue, regardless of its role in tumorigenesis, as well as having robust immunogenic properties.</p><p>CMV offers a plethora of possible targets, as it is the largest known DNA virus that infects humans, yet very little is known about its biological significance in glioblastoma pathogenesis as well as the most efficacious and immunogenic targets for immunotherapeutic development. </p><p>We have been able to elucidate more thoroughly the feasibility and potency of an immunologic platform targeting CMV within glioblastoma utilizing a multi-antigen multi-component peptide based strategy that demonstrated significant immunogenicity and anti-tumor activity in pre-clinical models utilizing various assays. We have also developed several sensitive and specific detection methodologies including: 1) custom gene expression microarrays, 2) multiplex real time quantitative polymerase chain reaction (RT-qPCR) assays, 3) a massively parallel RNA deep sequencing platform, and 4) immunological assays. We have also successfully determined the capacity for endogenous CMV gene expression to be maintained in primary glioblastoma cell lines as well as examining the preponderance of CMV gene expression in a subpopulation of glioma stem cell-like cells, the slow cycling GBM cells established from primary tumor tissues, in an attempt to illuminate some of the biologic underpinnings of CMV with respect to GBM pathogenesis.</p><p>Taken together, these data lay the groundwork for the development of a more efficacious vaccination strategy targeting CMV in GBM. The screening strategies employed throughout this work will allow for an accurate antigenic profile of CMV in GBM which will subsequently permit the design of a more robust peptide vaccine for the next generation of cancer vaccine. We have also begun to describe some of the interesting biologic phenomena associated with CMV in GBM, as our results demonstrate continued viral gene expression in glioma stem cell-like cell populations indicating viral tropism for certain cell types.</p> / Dissertation

Les métastases osseuses représentent un enjeu majeur de santé publique en raison de leur impact négatif sur la qualité de vie des patients mais également en raison de l’absence de traitements curatif. De nouvelles pistes thérapeutiques sont explorées dont l’immunothérapie anti-cancéreuse. En tant que principales responsables du recrutement leucocytaire, les chimiokines représentent des outils potentiels dans cette approche thérapeutique. La chimiokine fractalkine (CX3CL1) est impliquée dans de nombreux mécanismes physiologiques et pathologiques, dont le métabolisme osseux, la réponse immunitaire anti-tumorale mais également l’adressage et le développement tumoral, et ce de manière différentielle selon la forme considérée de cette chimiokine. En effet, CX3CL1 a la particularité d’exister sous deux formes : membranaire atypique (propriétés d’adhésion cellulaire) et soluble, typique des chimiokines (propriétés de chimioattraction). La mise en place d’un modèle syngénique murin de métastases osseuses expérimentales de carcinome pulmonaire nous a permis d’étudier l’effet de la forme soluble de CX3CL1 sur le développement métastatique en site osseux. L’expression ectopique de CX3CL1 soluble dans les cellules tumorales pulmonaires a conduit à une diminution de leur potentiel tumorigénique, une diminution de la résorption osseuse associée à une modification du ratio OPG/RANKL en faveur d’un phénotype ostéoblastique et à une modification du recrutement leucocytaire intratumoral en faveur d’une réponse immunitaire anti-tumorale. Outre l’importance de CX3CL1 dans le remodelage osseux, ce travail souligne le rôle essentiel du microenvironnement immunitaire dans la progression tumorale. Dans ce contexte, la forme soluble de CX3CL1 pourrait représenter un outil prometteur dans l’arsenal thérapeutique des métastases osseuses / Bone metastases represent a major public health issue due to their negative impact on patient’s quality of life as well as the current lack of curative treatment. New therapeutic leads are being investigated, among which is the anti-cancer immunotherapy. As the main molecules responsible for leukocyte recruitment, chemokines appear as potential tools for this therapeutic approach. The chemokine fractalkine (CX3CL1) is implicated in numerous physiological and pathological mechanisms, including bone metabolism, antitumor immune response as well as tumor homing and proliferation, in a differential manner depending on the considered form of CX3CL1. Indeed, the particularity of CX3CL1 is that it can exist under two forms: an atypical membrane-bound form (strong cellular adhesion) and a chemokine typical soluble form (chemoattraction). The development of a mouse syngeneic model of lung cancer experimental bone metastases allowed us to study the effect of the soluble CX3CL1 on metastatic development in a skeletal location. The ectopic expression of soluble CX3CL1 in the lung cancer cells led to a decrease of their tumorigenic potential, a decrease of bone resorption associated with a shift of the OPG/RANKL ratio toward an osteoblastic phenotype and a modification of leukocyte tumor infiltration in favor of an antitumor immune response. In addition to the importance of CX3CL1 in bone remodeling, this study underlines the essential role of the immune microenvironment in bone tumor progression. In this context, the soluble CX3CL1 could represent a promising tool in the therapeutic arsenal of bone metastases.

In the history of cancer treatment, the immunotherapy is considered to be the most promising treatment approach. The idea behind this breakthrough is to stimulate the patient’s own immune system to recognize the cancer cells and destroy them. In this therapy, the antibodies are known to be powerful medications to activate the immune system in different ways. They circulate throughout the body until they discover a substance that body recognize as alien i.e. antigen and bind to them. Similarly, cancer cells often have molecules on their surface known as tumor-associated antigens. The researchers can design many clones of the antibody that only target a certain antigen type such as one found on tumors or cancer cells. Then, these are used as an effective drug for treating cancer. Thus, the antigen specific antibody interactions play a vital role in cancer immunotherapy. In this study, we propose a dynamic model to represent the population of antigens and antibodies in cancer patients; in particular we focus on the antigen-specific-antibody interactions to elicit an immune response that leads to the death of cancer cells. We formulate a terminal control problem where the schedule and doses of these antibodies are considered as control variables. The objective functional has been formulated as a measure of antigen population at the end of the treatment period. Pontryagin minimum principle (PMP) has been used to obtain the optimal control policies. For illustration, a series of numerical results is presented showing the effectiveness of immune therapy for cancer treatment corresponding to the different scenarios, choices of parameters and treatment periods. The results indicate that the control doses are followed by the emergence of antigen population. This approach would be potentially applicable to determine and prescribe the optimal doses and schedules for cancer patients.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Background: Clinical trial completion is critical for new cancer therapies. Premature trial termination or withdrawal is common and impairs progress. We assessed factors of early terminated/withdrawn oncology trials focusing on trials with immune checkpoint inhibitors (ICI), hypothesizing that the latter may be associated with lower rates of premature discontinuation. Materials and Methods: We reviewed all adult, intervention, oncology trials registered in ClinicalTrials.gov (November 16, 2011, to April 16, 2015) to identify all terminated/withdrawn trials and reasons for termination. Logistics regression model was used to identify factors associated with early termination/withdrawal. Discontinuation rate was compared in trials with and without ICI. Results: We identified 12,875 trials (35% industry funded, 12% federal funded), of which 8.5% were prematurely terminated (5%) or withdrawn (3.5%); the main reasons were poor accrual (33%) and logistical (24%). ICI trials (n = 350) had a nonsignificant lower rate of termination or withdrawal compared with all other oncology trials (5.4% vs. 8.5%; p =.9) and were less likely to discontinue due to poor accrual (nonsignificant difference: 21% vs. 33%; p =.4). ICI trials were also less likely to discontinue compared with all other oncology drug trials (e.g., chemotherapy, targeted inhibitors, antiangiogenesis, biologics; 5.4% vs. 7.9%, respectively, nonsignificant difference). The 4-year cumulative incidence of failing to complete for reasons unrelated to toxicity or efficacy was 18% (95% confidence interval 16%–20%). There was no association between annual incidence across different tumor types or accrual goal and rate of trial termination. Conclusion: Poor accrual represents the main cause of early cancer trial termination. Premature termination/withdrawal rate was not significantly lower in ICI compared with other trials. Clinical trial completion remains a high priority and can be influenced by provider and patient factors. Implications for Practice: Clinical trial completion is critical for new cancer therapies. Premature trial termination or withdrawal is common and impairs progress. This study assessed factors of early terminated/withdrawn oncology trials, focusing on trials with immune checkpoint inhibitors (ICI), and found that poor accrual represents the main cause of early cancer trial termination. Premature termination/withdrawal rate was not significantly lower in immune checkpoint inhibitor trials compared to other trials. The discussion herein is focused on measures taken by the National Cancer Institute and other institutions to improve clinical trial accrual and prevent premature clinical trial discontinuation. / Revisión por pares