Thesis (Ph. D.)--University of Hong Kong, 1998. / Includes bibliographical references.

Successful adoptive immunotherapy (AIT) for cancer relies on the infusion of in vitro expanded, tumor-reactive lymphocytes with a goal of generating productive tumor immunity. Previously, our lab has developed a protocol to activate selectively tumor-reactive T lymphocytes in vitro using two pharmacologic agents, bryostatin-1 and ionomycin. Following the pharmacological stimulation, conventionally, IL-2 is added to stimulate in vitro proliferation. In this report, alternate cytokines from the common cytokine receptor γ-chain family, namely IL-7 and IL-15, were explored as the alternative cytokine supplements. We found that tumor DLN cells activated in vitro with B/I and cultured in IL-7/15 alternate common γ-chain cytokines expanded better than IL-2 cultured cells. Furthermore, immunosuppressive myeloid-derived suppressor cells from the tumor microenvironment were targeted with a chemotherapeutic agent, gemcitabine. Despite combining gemcitabine and the T lymphocytes expanded in IL-7/15, AIT failed to induce regression of large established 4T1 mammary flank tumors.

Foster and adoptive parents are crucial in the child welfare system, with the large number of foster children in the system at any time. Same-sex foster and adoptive homes are underrepresented in the child welfare system, despite the shortage and need for more certified foster and adoptive homes. There are limited studies documenting the experiences of gay and lesbian foster and adoptive parents. Some research has demonstrated that "non-traditional," or same-sex couples are met with more obstacles to become certified foster and adoptive parents, in comparison to their heterosexual counterparts. This qualitative study explores the experiences of same-sex foster and adoptive parents during the certification process. The findings suggest that social workers need to gain more knowledge regarding the values and practices of same-sex families, provide resources specific to same-sex family challenges, be sensitive to the unique circumstances of same-sex families, and most importantly, treat same-sex couples equally during the foster and adoptive certification process. Further research is needed looking at the areas of Family Court and judges' rulings, as well as social workers' perceptions in working with same-sex foster and adoptive parents.

Currently, in most situations, the autologous immune system is unable to eradicate the residual leukemic burden persisting after chemo-radiotherapy, but a balance can be established between leukemic and immune cells leading to a clinical remission for several months or years. If this balance is broken, a clinical relapse can occur. The high incidence of relapses in human cancers demonstrates the frequent inefficacy of the immune system to control these residual cells. In this context, allogeneic hematopoietic stem cell transplantation (HSCT) has been proven to be the most effective way to reinforce the immune reaction against leukemia, graft-versus-leukemia (GVL) effect and, so, achieve a definitive eradication of the residual disease in a significant proportion of patients. Indeed, the whole concept of HSCT evolved from an organ transplant concept (to replace a defective ill organ with a new healthy one) to the concept of creating an extraordinary immunotherapeutic platform in which the donor immune system contributes to the eradication of the residual leukemic cells. Thus, the past and present issues remain those of finding the best immunomodulatory modalities to achieve a full engraftment, a powerful GVL effect and no or moderate graft-versus-host disease (GVHD). Different ways to reach this goal, such as post transplant cytokine modulation, specific or global cellular depletion of the graft and post transplant global or specific donor immune cell add-backs, are still extensively studied. Nevertheless, the persistent high relapse rate (RR) observed in leukemia patients after HSCT remains the most important cause of death before transplant-related toxicities. Moreover, since only about 40 to 70% (depending on the ethnic context) of patients with high-risk hematological malignancies, eligible for allogeneic HSCT, have a fully HLA-matched sibling or matched unrelated donor (MUD), a great deal of effort has been invested to make the use of an alternative haploidentical sibling donor feasible. The advantage of this procedure is the immediate availability of a donor for almost all patients. The aim of the work described in this thesis has been to implement a strategy to transplant a patient using a HLA haploidentical donor. The strategy is to try to improve DFS that could be applied both in the autologous or allogeneic context: first, by using nonspecific immune manipulation post transplant and then, by developing specific strategies directed against leukemia antigens. Particularly in the allogeneic situation, the aim was to increase the GVL effect without inducing or aggravating the deleterious GVHD. The first part of this thesis described our own clinical results, consisting of three consecutive phase I/II studies, in which we tried to determine the feasibility of giving prophylactic donor lymphocyte infusions (DLI) post transplant and the effect of replacing granulocyte colony-stimulating factor (G-CSF), typically used to speed up neutrophil recovery, with granulocyte macrophage colony-stimulating factor (GM-CSF), which is known for its immunomodulatory properties. The slow immune reconstitution in haploidentical transplant is chiefly responsible for the high incidence of early lethal viral and fungal infections, and most probably for early relapses; therefore, we sought to accelerate and strengthen the post transplant immune reconstitution without increasing the GVHD rate. Thus, we have studied the impact of post transplant growth factor administration and of unselected DLI in haploidentical transplant. We have also implemented, in our center, anti-cytomegalovirus (CMV) specific T cell generation and infusion to improve anti-CMV immune reconstitution. Since then, our results have been pooled in a multi-center analysis performed by the European Bone Marrow Transplantation group (EBMT) allowing us to compare our results with those of the entire group. We have also participated in the design of an ongoing study aimed at selectively depleting the graft from alloreactive T cells, and improving post transplant T cell add-backs. In our attempts to generate and expand ex vivo lymphocytes (directed against pathogens (CMV) and leukemia-associated antigens, Wilms' tumor gene 1 (WT1) and to use them in vivo, we found inconsistent results (in the case of WT1) using classical clinical grade dendritic cells (DC) generated and matured in bags, as was the case for the majority of the teams worldwide. This led us to question the full functionality of these DC and we undertook a thorough comparative analysis of DC generated and differentiated in bags and in plates (typical for most pre-clinical studies). This analysis showed us that one cannot transpose pre-clinical studies (using culture plates) directly to clinical protocols (generally using clinical grade culture bags) and that DC generated in bags are functionally deficient. We learned that, if we want to use a DC vaccine to improve the GVL effect in haploidentical transplant, we will have to be careful about the technique by which they are generated. To improve immunotherapeutic approaches, the understanding of the mechanisms underlying tumor tolerance and how to manipulate them is critical in the development of new effective immunotherapeutic clinical trials. This is why we currently focus on how to obtain effective in vivo anti-leukemia immune reactions using an ex-vivo manipulated product to trigger the immunotherapeutic response. More specifically, we are analyzing the impact of regulatory T cell (Tregs) depletion and function for an adequate anti-leukemic immune response. This pre-clinical work aims at improving the outcome of leukemia patients who have relapsed and been put back into second remission and at decreasing the RR after HSCT, especially in the field of haploidentical transplantation. In conclusion, haploidentical transplantation has become a valuable tool. The results are at least similar to those obtained using MUD when performed in the same group of patients. Specific immunomodulation post transplant can affect events such as GVHD and GVL, but clinically we are still at the level of nonspecific manipulations. It is our hope that ongoing pre-clinical work will enable us to perform specific anti-pathogen and anti-leukemia immune manipulation that will favorably influence the patient outcome. / Dans la majorité des situations, le système immunitaire autologue est incapable d’éradiquer les cellules leucémiques résiduelles qui échappent à la radiothérapie et à la chimiothérapie, cependant un équilibre peut s’établir entre les cellules leucémiques et immunitaires aboutissant à une rémission pouvant durer plusieurs mois ou années. Si cet équilibre se rompt, une rechute clinique peut se déclarer. Dans ce contexte, il est prouvé que la greffe allogénique de cellules souches hématopoïétiques est le moyen le plus efficace de renforcer les réactions immunitaires contre la leucémie par la réaction du greffon contre la leucémie et ainsi d’obtenir une éradication définitive de la maladie résiduelle chez un nombre significatif de patients. En effet, le concept global de l’allogreffe de cellules souches hématopoïétiques a évolué du concept de transplantation d’organe (remplacement d’un organe malade par un nouvel organe sain) vers celui de créer une extraordinaire plateforme d’immunothérapie à travers laquelle le système immunitaire du donneur contribue à l’éradication des cellules leucémiques persistantes. Donc, la problématique reste celle de trouver les meilleures modalités d’immunomodulation pour achever une prise du greffon, un effet anti-leucémique puissant du greffon, et l’absence ou un minimum d’effet du greffon contre l’hôte. Différentes stratégies existent pour atteindre cet objectif, comme l’utilisation de cytokines pour moduler la reconstitution immunitaire, des déplétions cellulaires globales ou spécifiques du greffon et l’infusion de cellules immunes «globales» ou spécifiques du donneur après greffe. Ces stratégies sont encore largement à l’étude. Néanmoins, la persistance d’un taux de rechute élevé observé chez les patients leucémiques, après allogreffe reste la cause principale de décès, avant celle liée à la toxicité de la greffe. De plus, étant donné que seulement environ 40 à 70% (dépendant de l’origine ethnique) des patients avec une hémopathie à haut risque, éligibles pour une greffe allogénique, ont un donneur familial ou non familial complètement HLA compatible, des efforts importants ont été développés pour rendre faisable l’utilisation de donneurs familiaux alternatifs, haploidentiques. L’avantage de cette approche est l’accès immédiat à un donneur pour quasiment tous les patients. Le but du travail décrit dans cette thèse a été l’implémentation d’une stratégie d’allogreffe utilisant un donneur haploidentique. Le travail vise également à développer de façon plus large des stratégies qui peuvent améliorer le taux de survie sans rechute, non seulement dans le contexte des greffes haploidentiques, mais également dans le cadre des greffes allogéniques en général, ainsi que dans les situations autologues : premièrement, par la manipulation immunitaire non spécifique après greffe et ensuite par le développement de stratégies spécifiques dirigées contre des antigènes leucémiques. En particulier dans la situation allogénique, le but a été d’augmenter l’effet du greffon contre la leucémie sans induire ou aggraver l’effet délétère du greffon contre l’hôte. La première partie de la thèse décrit les résultats cliniques de notre propre protocole de greffe haploidentique, qui a consisté en trois études consécutives de phase I/II. Dans ces études, nous avons voulu déterminer la faisabilité de réaliser des infusions prophylactiques de lymphocytes du donneur après transplantation, et l’impact du remplacement du « granulocyte colony-stimulating factor » (G-CSF), largement utilisé pour permettre une récupération en polynucléaires neutrophiles plus rapide, par du « granulocyte-macrophage colony-stimulating factor » (GM-CSF), lequel est connu pour ses propriétés immunomodulatrices différentes. La reconstitution immunitaire très lente après greffe haploidentique est majoritairement responsable de l’incidence élevée de décès par infections virales et fungiques précoces, et très probablement des rechutes précoces. C’est pourquoi nous avons cherché à accélérer et à renforcer la reconstitution immunitaire post-greffe sans augmenter la fréquence de réaction du greffon contre l’hôte. Nous avons donc étudié l’impact de l’administration de facteurs de croissance et l’infusion de lymphocytes non sélectionnés du donneur en post greffe haploidentique. Nous avons également implémenté dans notre centre, la génération et l’infusion de lymphocytes T spécifiques anti-cytomégalovirus (CMV) afin d’améliorer la reconstitution immunitaire anti-CMV. D’autre part, nos résultats ont été regroupés dans une étude multicentrique menée par le groupe européen de transplantation de moelle osseuse (EBMT), ce qui nous a permis de comparer nos résultats avec ceux de l’entièreté du groupe. Nous avons parallèlement participé à la conception d’une étude actuellement en cours ayant pour but d’améliorer la reconstitution immunitaire après greffe par la déplétion sélective du greffon en lymphocytes T alloréactifs et par l’infusion après greffe de lymphocytes T du donneur également sélectivement déplétés en lymphocytes T alloréactifs. Afin d’optimaliser l’effet anti-leucémique du système immunitaire, nous avons débuté un protocole de vaccination par cellules dendritiques (DCs). Ces cellules dendritiques étaient chargées en lysat de blastes leucémiques dans le cas de patients présentant au diagnostic une leucémie aigue surexprimant l’oncogène 1 de la tumeur de Wilms (WT1). Néanmoins dans nos travaux de génération et d’expansion ex-vivo de lymphocytes T spécifiques de l’antigène WT1, utilisant les DCs de grade clinique, générées et maturées en poches, nous avons rencontré des résultats inconsistants, comme c’était le cas dans la majorité des protocoles cliniques internationaux de vaccination. Nous nous sommes alors posé la question de la fonctionnalité globale de ces cellules et nous avons entrepris une analyse comparative poussée des DCs générées et différenciées en poches ou en plaques. Les DCs générées en plaques sont celles utilisées dans la plupart des travaux précliniques. Cette analyse nous a montré que l’on ne pouvait pas directement transposer les résultats précliniques basés sur des DCs générées en plaques dans des protocoles cliniques basés sur des DCs générées en poches, car ces dernières présentent des déficits fonctionnels importants. Nous avons appris que si l’on voulait utiliser un vaccin à base de cellules dendritiques pour améliorer l’effet du greffon contre la leucémie dans les greffes allogéniques, nous devions être très attentifs quant au protocole utilisé pour la génération de ces vaccins cellulaires. Pour améliorer les approches immunothérapeutiques, la connaissance des mécanismes qui établissent la tolérance tumorale et des façons de manipuler ceux-ci, est critique dans le développement de nouveaux protocoles efficaces. C’est pourquoi nous nous concentrons actuellement sur les conditions nécessaires à l’obtention in vivo d’une réaction immune anti-leucémique efficace lors de l’utilisation d’un produit cellulaire manipulé ex vivo. Plus spécifiquement, nous analysons l’impact de la déplétion en lymphocytes T régulateurs (Tregs) sur la réponse anti-leucémique. Ce travail préclinique a pour but d’améliorer le devenir de patients leucémiques qui ont rechutés et ont été mis en seconde rémission, ainsi que de diminuer le taux de rechute après allogreffe, spécifiquement après greffe haploidentique. En conclusion, la transplantation haploidentique est actuellement un outil précieux pour de nombreux patients. Les résultats sont au minimum similaires à ceux qui sont obtenus par les greffes non-familiales HLA identiques lorsqu’elles sont pratiquées dans les mêmes groupes de patients. L’immunomodulation spécifique après greffe peut affecter des événements comme la réaction du greffon contre l’hôte et la réaction du greffon contre la leucémie, mais en pratique clinique nous en sommes encore au niveau de la manipulation aspécifique. Nous espérons que les travaux précliniques actuels vont nous permettre d’appliquer des stratégies spécifiques et d’obtenir une manipulation immune anti-leucémique qui aura une influence favorable significative sur le devenir des patients.

Thesis (M.A.)--York University, 1997. Graduate Programme in Interdisciplinary Studies. / Typescript. Includes bibliographical references (leaves 180-188). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL:http://wwwlib.umi.com/cr/yorku/fullcit?pMQ27368.

Thesis ( Ph.D.) -- University of Texas at Arlington, 2008.

Malignant melanoma is a common type of solid tumor that causes high cancer-related mortality in young adults of Northern Europe. The incidence of melanoma increases rapidly which renders us a special responsibility to investigate this disease in depth. One recent promising approach to treat malignant melanoma is adoptive cell therapy with tumor-directed autologous T cells. This thesis aims to improve this therapy in four different studies. We first sought to establish a protocol for the assessment of melanoma-specific T-cell cultures in order to screen for optimal specificity and reactivity in a robust, reliable and simple manner. The conclusion was that reactive cells could be found in a majority of patients and could be screened for specificity by stimulation with melanoma cell lines. In the next study, 28 melanoma patients with advanced disease were treated with autologous tumor-infiltrating T cells. Objective responses (18%) including one sustained complete response were observed. This is the first study in cancer patients with autologous T cell transfer combined with low-dose s.c. IL-2 as supportive cytokine. In the following two studies we wanted to improve management and culture conditions of the T cells. When investigating methods for improved handling and preservation of large numbers of T cells, we observed that freeze-thawing of T cells could impair the metabolic activity of the T cells. Another conclusion was that rapid expansion of T cells could lead to loss of antigenic specificity and apoptosis. These adverse effects could be prevented with short time recovery. In order to improve expansion methods, mass expansion of T cells in an automated bioreactor was evaluated. We concluded that the bioreactor is suitable for this task and allows for higher cell densities and absolute cell numbers compared to traditional culturing conditions without influencing cell phenotype or reactivity. Taken together, my current studies present guiding principles and encouragement for the further development of immunotherapies for treatment of patients with malignant melanoma.

This thesis is primarily an analysis of two unstructured questions from a mail questionnaire sent, in 1956, to adopters in Quebec, Ontario, New York, Ohio and California. The method we have used is that of content analysis which is described in another section of this introduction. [...]

Infertile heterosexual couples comprise the majority of those pursuing parenthood via adoption. While research into the experience of adoptive parenthood has focused on adoptive mothers and couples, the research on either group has not fully captured the experience of adoptive fathers. The present study was aimed at understanding how men perceive adoption, and its pursuit, following failed infertility treatment. Sixteen established and prospective adoptive fathers were recruited to participate in individual semi-structured interviews. Narrative analysis was used to evaluate the men’s meaning-making process related to fatherhood. The men told stories which indicated they both believed and countered western culture’s master narrative that fatherhood is constructed via genetic reproduction. I elaborate on the implications of these narratives for understanding the experience of adoptive fatherhood in specific, and fatherhood in general. Following this, recommendations are made for infertility treatment practitioners, adoption service providers, and future researchers based on these implications.

The purpose of this thesis was to suggest exemplary factors of adoption ministry programs to successfully support adoptive parents who have experienced difficulties in their adoptive family life by examining adoptive parents' practical needs and practical consideration of adoption ministry programs in adoption ministry churches. Chapter 1 presents the research concerns, introduces the context of the research problem, and explains key words related to the research. Chapter 2 consists of literature reviews related to adoption and adoption ministry. This chapter provides biblical, theological, and practical perspectives on adoption and adoption ministry as well as examines the present circumstance of adoption ministry in Korean churches. Chapter 3 explains the methodological design of the study. This chapter contains an overview of the research design, and an explanation of the research sample, the research instrumentation, and the procedures of the research. Chapter 4 analyzes the data collected from the study through a general demographic questionnaire and an open-ended essay questionnaire. The study surveyed and interviewed two sample groups. According to the comparison of responses between adoptive parents and adoption ministers, in general, I found that most adoptive parents understood the biblical, theological, and practical meaning of adoption and that adoption ministry positively influenced the church. Adoptive parents and adoption ministers must play a key role in creating an adoption culture in the church, but the leader of adoption ministry should be the senior pastor. Chapter 5 discusses the research implications and how those implications apply to the adoption ministry in Korean churches. The study aimed to effectively support adoptive parents through adoption ministry programs. The results offer several exemplary factors of adoption ministry programs such as education, counseling, adoptive family meeting, and financial support.