American Indian and Alaska Native substance use treatment: Barriers and facilitators according to an implementation framework.

INTRODUCTION: Substance use disorder (SUD) and overdose deaths are higher in the American Indian and Alaska Native (AIAN) population than in other racial/ethnic groups. Multi-level gaps hinder SUD treatment for AIAN patients. Few studies have engaged front-line clinicians and administrators of SUD treatment programs serving AIAN patients to identify barriers and facilitators to improve the implementation of effective treatment. METHODS: We conducted key informant interviews with a diverse sample of providers and administrators of SUD treatment programs across California regarding barriers and facilitators to treatment for AIAN patients. An AIAN-majority community advisory board (CAB) guided the development of an interview guide and helped to recruit respondents from five types of SUD programs statewide. Using ATLAS.ti, the research team coded interviews and classified emergent themes as barriers and facilitators related to Outer, Inner, and Individual domains of the Consolidated Framework for Implementation Research (CFIR). RESULTS: Representatives of 13 of 15 invited SUD treatment programs participated and 9 of the 13 interviewed self-identified as AIAN. Related to Outer Setting barriers from coded interviews, a dominant barrier was policies that defund or underfund SUD treatment, especially detoxification centers. Outer Setting facilitators included consistent Indian Health Service (IHS) eligibility criteria, judicial system connections for direct treatment access, and community programs advocating SUD treatment. Key themes related to barriers for the Inner Setting were limited bed capacity, poor coordination of intake and care, and lack of telehealth technology. Facilitators integrated mental health, linkage to external resources, and culturally centered care. Individual-level barriers were negative attitudes such as SUD stigma, distrust of governmental programs, and lack of transportation while individual engagement was facilitated by programs addressing negative attitudes and providing telemedicine for remote care. CONCLUSION: The public health threat of SUD for the AIAN population mandates the implementation of interventions and policies that facilitate care. This qualitative study with primarily AIAN clinical leaders of SUD treatment highlights opportunities to improve care at multiple CFIR levels, focusing on capacity, coordination, culturally congruent care, and community initiatives to promote engagement.

Transplantation of autologous bone marrow pre-loaded ex vivo with oncolytic myxoma virus is efficacious against drug-resistant Vk*MYC mouse myeloma.

Multiple myeloma (MM) is a hematological malignancy of plasma cells that remains incurable despite significant progress with myeloablative regimens and autologous stem cell transplantation for eligible patients and, more recently with T cell redirected immunotherapy. Recently, we reported that ex vivo virotherapy with oncolytic myxoma virus (MYXV) improved MM-free survival in an autologous-transplant Balb/c mouse model. Here, we tested the Vk*MYC transplantable C57BL/6 mouse MM model that more closely recapitulates human disease. In vitro, the murine bortezomib-resistant Vk12598 cell line is fully susceptible to MYXV infection. In vivo results demonstrate: (i) autologous bone marrow (BM) leukocytes armed ex vivo with MYXV exhibit moderate therapeutic effects against MM cells pre-seeded into recipient mice; (ii) Cyclophosphamide in combination with BM/MYXV delays the onset of myeloma in mice seeded with Vk12598 cells; (iii) BM/MYXV synergizes with the Smac-mimetics LCL161 and with immune checkpoint inhibitor α-PD-1 to control the progression of established MM in vivo, resulting in significant improvement of survival rates and decreased of tumor burden; (iv) Survivor mice from (ii) and (iii), when re-challenged with fresh Vk12598 cells, developed acquired anti-MM immunity. These results highlight the utility of autologous BM grafts armed ex vivo with oncolytic MYXV alone or in combination with chemotherapy/immunotherapy to treat drug-resistant MM in vivo.

Autologous Transplantation Using Donor Leukocytes Loaded Ex Vivo with Oncolytic Myxoma Virus Can Eliminate Residual Multiple Myeloma.

Multiple myeloma (MM) is a hematological malignancy of monoclonal plasma cells that remains incurable. Standard treatments for MM include myeloablative regimens and autologous cell transplantation for eligible patients. A major challenge of these treatments is the relapse of the disease due to residual MM in niches that become refractory to treatments. Therefore, novel therapies are needed in order to eliminate minimal residual disease (MRD). Recently, our laboratory reported that virotherapy with oncolytic myxoma virus (MYXV) improved MM-free survival in an allogeneic transplant mouse model. In this study, we demonstrate the capacity of donor autologous murine leukocytes, pre-armed with MYXV, to eliminate MRD in a BALB/c MM model. We report that MYXV-armed bone marrow (BM) carrier leukocytes are therapeutically superior to MYXV-armed peripheral blood mononuclear cells (PBMCs) or free virus. Importantly, when cured survivor mice were re-challenged with fresh myeloma cells, they developed immunity to the same MM that had comprised MRD. In vivo imaging demonstrated that autologous carrier cells armed with MYXV were very efficient at delivery of MYXV into the recipient tumor microenvironment. Finally, we demonstrate that treatment with MYXV activates the secretion of pro-immune molecules from the tumor bed. These results highlight the utility of exploiting autologous leukocytes to enhance tumor delivery of MYXV to treat MRD in vivo.