A major obstacle in the implementation of adoptive cell therapy (ACT) for solid tumors is CD8+ T cell quantity and functional quality. In order to address this issue, the ACT field has directed considerable effort toward the generation of less-differentiated memory T cells (Tm), which demonstrate superior effector function and engraftment over effector T cells. An obstacle in using Tm for ACT is their requirement for in vivo activation before full effector function can be acquired. We sought to determine if a rhabdovirus expressing a defined tumor antigen (i.e. a rhabdoviral oncolytic vaccine) could activate adoptively-transferred Tm in vivo and eliminate established tumors. We used ex vivo cultured DUC18 TCR-transgenic Tm combined with a rhabdoviral oncolytic vaccine to target established CMS5 fibrosarcomas in both balb/c and NRG mice, and we compared the efficacy of the combination treatment versus monotherapies. Our data demonstrate that the rhabdoviral oncolytic vaccine was capable of expanding adoptively-transferred Tm in order to eliminate established tumors. Furthermore, synergy between ACT and oncolytic vaccination was required for optimal therapeutic outcome. Interestingly, we observed a population of endogenous, tumor-primed lymphocytes which appeared to be required for complete tumor elimination and subsequent memory formation. This was in contrast to the current consensus in the ACT field which is that endogenous lymphocytes are detrimental to therapeutic outcome, thus necessitating lymphodepletion prior to the commencement of therapy. Our data suggest that endogenous lymphocytes may be a beneficial cell population which is overlooked by current approaches to ACT. / Thesis / Master of Science (MSc) / Current approaches to the T cell therapy of cancer are hindered by poor cell quality. It is simple to grow higher quality T cells, but it is difficult to grow very large numbers of them. Furthermore, higher quality T cells need a signal in order to “switch on” before they can start killing cancer cells. Here, we use a cancer-targeting virus as a signal for these cells to activate, grow to very large numbers in the patient, and destroy their tumor. Our vaccine also switches on other immune cells in the patient, which help guarantee the destruction of the tumor. The significance of this work is that it will improve T cell therapy for cancer by opening the possibility of using higher-quality T cells which are much better at killing cancer than the currently used type of T cells.

Cancer immunotherapy has gained attention in recent years for its successes in potentiating immune responses that can elicit tumor control. In particular, adoptive cell therapy (ACT), which involves the autologous/allogeneic transplant of ex vivo-cultivated tumor-specific T lymphocytes, can mediate potent tumor recognition and killing; however, durable clinical responses are often difficult to obtain in solid tumors. Solid tumors and their unique microenvironments have the capacity to evade and suppress antitumor immune responses and represent significant hurdles for effective ACT. Recently, we have discovered that chemical inhibition of histone deacetylases via MS-275 (Entinostat) during ACT can subvert tumor resistance to foster potent, broad-spectrum antitumor immunity. Overall, the work described supports the efficacy of ACT in the treatment of immunosuppressive, solid tumors; however, consistency in durable clinical outcomes can only be achieved through the concurrent therapeutic targeting of tumor resistance mechanisms. This thesis uses pre-clinical models to describe how tumor resistance to ACT can manifest, and demonstrates that concurrent MS-275 delivery drives extensive immunomodulation to promote sustained tumor clearance. This includes: 1) The polarization of tumor-infiltrating myeloid cells into cytotoxic effectors with the ability to reject immune escape variants 2) The inflammatory remodeling of the tumor microenvironment to potentiate epitope spreading against secondary tumor antigens 3) The transcriptional reprogramming of adoptively transferred T cells to overcome tumor-burden-dependent exhaustion We expect that the results will help facilitate the development of next-generation ACT platforms that will feature strategies for multi-mechanistic perturbation of tumor resistance. / Thesis / Doctor of Philosophy (PhD) / The host immune system has the ability to recognize and destroy tumor cells. Therapeutic platforms that leverage antitumor immune cells, specifically T cells, have shown potency in the elimination of cancer. In the clinic, cancer immunotherapies have demonstrated early success against hematological malignancies; however, are unreliable in the treatment of solid tumors. Solid tumors utilize intrinsic and adapted mechanisms of resistance to mitigate the effectiveness of cancer immunotherapy. This thesis pursues research questions aimed at understanding how tumors resist immunotherapy, what mechanisms are utilized, and how to overcome these obstacles. We anticipate that these results will contribute to the development and incorporation of strategies to subvert tumor resistance and potentiate T cells against solid tumors.

No description available.

Studien undersöker och analyserar vilket stöd svenska adoptionsorganisationer erbjuder adoptivföräldrar som adopterar barn utan respektive med funktionsnedsättning samt analyserar vilken betydelse stödet kan ha utifrån ett psykologiskt perspektiv. Adoption sker via auktoriserade adoptionsorganisationer som styrs av lagar och konventioner för att se till barnets bästa i adoptionsprocessen. Utifrån att det finns ett behov av mer forskning samt utveckling inom adoptions området för att kunna öka förståelsen för adoptivföräldrar som adopterar barn med funktionsnedsättning. Resultatet visade att stödet är likvärdigt för adoptivbarn med respektive utan funktionsnedsättning vilket från tidigare forskning visar på en stor brist som har en inverkan på adoptivföräldern och adoptivbarnet anknytning och utveckling. / This study aims to investigate and analyze the support that swedish adoption agencies offer adoptive parents who adopt children with and without disabilities, and analyzes the importange of this support from a psychological perspective. Adoption takes place through authorized adoption organizations that are governed by laws and conventions to ensure the best interests of the child in the adoption process. Given the need for more research and development within the field of adoption to increase understanding of adoptive parents who adopt children with disabilities. The reault of the study showed that the support is equal for adopted children with and without disabilities, which, according to previous research, indicates a significant deficiency that impacts the attachment and development of both adoptive parents and adopted children.

This study was done to examine prospective adoptive parents' perceptions of one particular group of special needs children waiting for adoption: those children with developmental disabilities. The results will give social workers information that will help provide training and informational meetings to prosepctive parents in regard to the child's age and developmental disabilities.

Adoptive parents need to be able to reflect on the interaction with the child, both from the perspective of their own relational experience with the child and from the perspective of the previous experience of the child. This essay explores five adoptive parent´s thoughts and feelings about their children’s background. It also looks into how they think that the children’s background influences their way of expressing their needs and how this makes the parents feel. Data has been collected through semi-structured interviews which have been analyzed using thematic analysis. The thoughts and feelings around the children’s background mainly concerns how the children were taken care of prior to the adoption and the birth parents. The parents expressed feelings of sadness and sorrow regarding how the children were taken care of prior to the adoption. Thinking of how it could have been for the children gave rise to strong emotions. The parents expressed sympathy and sorrow but also rivalry, envy and anger towards the birth parents. They describe different behaviors’ and expressions that the children have and how they think that these may be related to the experiences the children had prior to the adoption. The parents describe what the children’s behaviors and expressions arouse within themselves. They tell about strong somatic and dissociative reactions, feelings of guilt, uncertainty and insufficiency. The parents also describe how the interaction with their children reminds them of painful experiences from their own childhood. The accounts show the importance of the parents´ ability to mentalise and how they think about needs that the children don´t express.

Reactive attachment disorder (RAD) is characterised by severely underdeveloped or absent attachment between a child and a caregiver. Adopted children who have experienced adverse early experiences prior to adoption may have lacked opportunities to form selective attachment relationships and, in rare cases, may have a diagnosis of reactive attachment disorder. The needs of adoptive families rearing children with special needs, such as children with a RAD diagnosis, are unique and it is crucial to understand the experiences of the families in order to increase the understanding of how to provide support and adequate services and interventions that respond to the needs of the families. Previous research focusing on adoptive parents’ experiences rearing children with a RAD diagnosis is scarce. Therefore, this systematic literature review aimed to explore their experiences. After a comprehensive literature search, seven articles that addressed the study aim and met the predefined inclusion criteria were included. A thematic synthesis was carried out to combine the results of the included articles. The findings suggest that adoptive families rearing children with a RAD diagnosis experience a wide range of challenges in their everyday lives, such as a lack of social network support and adequate support, services and interventions from professionals and service providers. Some facilitative factors, such as adoptive parents’ willingness to stay committed to their children, were found. Further research is needed to find out effective interventions to address the complex challenges adoptive families and their children with a RAD diagnosis experience. Study limitations and methodological considerations are discussed.

'Closed stranger' adoption in Aotearoa / New Zealand from approximately 1940 to 1990 involved the practice of a complete break between the birth mother and her child and the legal transfer of the child to adoptive parents. In Aotearoa / New Zealand between 1940 and 1990, 108,899 adoptions took place, and most consisted of ‘closed stranger’ adoptions. These adoptions have caused much joy as well as some heartache for parties involved in the experience namely, birth mothers, adoptees and adoptive mothers and their whānau. This thesis reports original research which aims to investigate the unique experiences of Māori adoptive mothers in the 'closed stranger' adoption period and enable the impact of legal adoption on these Māori women who have not previously warranted research, to be valued. A qualitative methodology, Māori-centred research and unstructured kanohi ki te kanohi (face to face) interviews were utilized to gather data from six Māori adoptive mothers. The intention of Māori centred research as its name suggests, is to locate Māori people and Māori knowledge at the centre of the research action. A thematic analysis utilizing interpretative phenomenological analysis (IPA) was used. The unique experiences of Māori women legally adopting in the ‘closed stranger’ adoption system were about whānau business, and grouped under that superordinate theme were experiences of ‘not blood’, land succession, naming and caring for whānau. The stigma of adoption resonated throughout the women’s narratives. As well, most of these Māori adoptive mothers found that they experienced ‘closed stranger’ adoption as a ‘rollercoaster of emotions’.

<p>The main focus of my thesis has been to develop protocols for generating antigen-specific cytotoxic T lymphocytes (CTLs) and T helper cells (T_H) for adoptive transfer to treat cytomegalovirus (CMV) disease and prostate cancer. CMV viremia is a severe complication in immunocompromised stem cell transplanted patients. Prostate cancer is a leading cause of death for men in Western countries. Although different in nature, CMV-infected cells and prostate cancer cells can both be eliminated through specific activation of the adaptive immune system. </p><p>To generate CMV pp65-specific T cells, I utilized dendritic cells (DCs) modified with an HLA-A*0201/pp65_495-503 peptide, a recombinant adenovirus coding for pp65, <i>in vitro</i> transcribed pp65 mRNA and a recombinant pp65 protein. Peptide stimulation yielded large numbers of peptide-specific CD8⁺ T cells with high lytic activity while adenovirus or mRNA stimulation resulted in the expansion of CTLs against multiple pp65 epitopes. The recombinant protein activated primarily CD4⁺ T_H cells. Stimulation with DCs co-modified with pp65 mRNA and pp65 protein simultaneously generated both pp65-specific CTLs and T_H cells. Such T cells would cover all pp65 epitopes while avoiding potential virus related biohazards. The mRNA/protein combinatory approach can be used to stimulate T cells <i>ex vivo</i> from virtually all stem cell donors for adoptive T cell transfer. </p><p>I have identified two immunogenic HLA-A*0201-restricted peptide epitopes from the prostate tissue antigen TARP. Repeated stimulations with TARP peptide-pulsed DCs yielded up to 20% TARP-directed CD8⁺ T cells even when starting from undetectable frequencies (<0.01%). The T cells could be sorted to 99% purity and expanded 1000-fold with retained specificity and activity. We also detected TARP-directed CD8⁺ T cells in the blood of prostate cancer patients. Therefore, TARP seems to have potential as antigen in DC vaccination or adoptive T cell therapy of prostate cancer. </p>

<p>In order to study internationally adopted delinquents, internationally adopted controls, delinquent controls and an additional group of healthy non-adopted, non-delinquent controls, the following tests were used: WISC/WAIS, TOL, WCST, a questionnaire, I think I am, ISSI, an attachment test, KSP, and SCL-90. In the register study, data were obtained from the registers of The National Board of Health and Welfare and Statistics Sweden and multivariate analyses were performed using logistic regression models. Odds ratios (OR) for different forms of out-of-home care placements were calculated.</p><p>It was found that the adopted delinquents had a significantly lower full scale IQ (WISC/WAIS) and significantly lower results on several measurements in the WISC /WAIS compared to the adopted controls. In addition, both groups of adoptees scored low in the WISC/WAIS subscale arithmetics when compared to the population mean. The adopted delinquents clearly had disruptive and infectious relations to their parents which was demonstrated in I think I am, ISSI, the attachment test and the questionnaire. The adopted controls demonstrated good relations to adoptive parents. When personality and self-perception were measured and analyzed in a two-way ANOVA, the results clearly pointed to ”delinquency” as the explaining factor to the variance of the results as opposed to ”adoption”. </p><p>Finally, the regression analyses of the register data demonstrated an OR of 3.0 (after adjustments for age and sex) for placements of intercountry adoptees in residental care from age 10 and an OR of 5.1 in model 2 (after adjustments for socio-demographic background variables). More over, higher child age at adoption, origin from Latin America, single parent adoption and maternal age above 35 at birth of the child were identified as significant predictors of out-of-home care from age 10.</p>