The translational gap for gene therapies in low- and middle-income countries.

Gene therapies are designed to address the root cause of disease. As scientific understanding of disease prevention, diagnosis, and treatment improves in tandem with technological innovation, gene therapies have the potential to become safe and effective treatment options for a wide range of genetic and nongenetic diseases. However, as the medical scope of gene therapies expands, consideration must be given to those who will benefit and what proactive steps must be taken to widen development and access potential, particularly in regions carrying a high disease burden.

Impact of training on knowledge, confidence and attitude amongst community health volunteers in the provision of community-based palliative care in rural Kenya.

OBJECTIVES: Existing literature suggests multiple potential roles for community health volunteers (CHVs) in the provision of palliative care (PC) in low- and middle-income countries. In Kenya the role of CHV in the provision of PC has not been reported. The objective of this study was to assess knowledge, confidence, attitude, and clinical practice of community health volunteers after attending a novel palliative care (PC) training program. METHODS: A total of 105 CHVs participated in a 3-day in person training followed by a 1-month in person and telephone observation period of the palliative care activities in the community. Structured questionnaires were used pre- and post-training to assess knowledge acquisition, impact on practice, and content delivery. A mixed method study design was conducted 12-month post training to assess impact on clinical practice. RESULTS: Immediately after training, CHV provided positive ratings on relevance and content delivery. In the month following training, CHVs evaluated 1,443 patients, referred 154, and conducted 110 and 129 tele consults with the patients and PC providers respectively. The follow up survey at 12 months revealed improved knowledge and confidence in various domains of palliative care including symptom and spiritual assessment and provision of basic nursing and bereavement care. Focus group discussions revealed the CHVs ability to interpret symptoms, make referrals, improved communication/ interpersonal relationships, spiritual intervention, patient comfort measures and health care practices as newly learned and practiced skills. CONCLUSIONS: We noted improved knowledge, new skills and change in practice after CHVs participation in a novel training curriculum. CHVs can make important contributions to the PC work force and be first line PC providers in the community as part of larger hub and spoke care model.

Implementation of a gene therapy education initiative by the ASGCT and Muhimbili University of Health and Allied Sciences.

There has been rapid growth in gene therapy development with an expanding list of approved clinical products. Several therapies are particularly relevant to patients in low- and middle-income countries. Moreover, investing in research and manufacturing presents an opportunity for economic development. To increase awareness of gene therapy, the American Society of Gene and Cell Therapy partnered with the Muhimbili University of Health and Allied Sciences, Tanzania, to create a certificate-bearing course. The goal was to provide faculty teaching in graduate and medical schools with the tools needed to add gene therapy to the university curriculum. The first virtual course was held in October of 2022, and 45 individuals from 9 countries in Africa completed the training. The content was new to approximately two-thirds of participants, with the remaining third indicating that the course increased their knowledge base. The program was well received and will be adapted for other under-resourced regions.

Telehospice for Cancer Patients Discharged from a Tertiary Care Hospital in Western Kenya.

CONTEXT: Worldwide, most patients lack access to hospice services. OBJECTIVES: Assess the feasibility of telephone monitoring (Telehospice) in providing symptom management for patients discharged from a tertiary care hospital in Western Kenya. METHODS: Inclusion criteria included adults with cancer no longer eligible for chemo-radiation and receiving opioid therapy. Thirty patients were enrolled in a weekly monitoring program assessing physical symptoms and patient and caregiver distress. The participants also had access to a 24-hour hotline. Symptom assessment included 18 questions with 8 from the African Palliative Outcome Scale. Participants were followed for eight weeks or until death or admission to an inpatient hospital or hospice. RESULTS: The primary objective was participation in weekly calls, and we obtained 100% participation. A secondary objective was the use of "comfort kits" which contained 30 doses of six medications. Most patients utilized one or more of the provided medications, with high usage of bisacodyl, paracetamol, and omeprazole. While 12% of weekly calls and 24% of hotline calls led to medication changes, participants continued to express worry and there was only a modest decrease in pain scores despite having morphine available throughout the follow-up period. Family confidence in providing care and access to information remained high. At the end of the eight-weeks of observation, eight participants were alive, 10 died at home, and 12 were admitted to an in-patient facility. CONCLUSION: Patient and family participation in Telehospice is feasible and may provide an interim solution to managing end-of-life patients who lack access to home hospice.

Meeting FDA Guidance recommendations for replication-competent virus and insertional oncogenesis testing.

Integrating vectors are associated with alterations in cellular function related to disruption of normal gene function. This has been associated with clonal expansion of cells and, in some instances, cancer. These events have been associated with replication-defective vectors and suggest that the inadvertent exposure to a replication-competent virus arising during vector manufacture would significantly increase the risk of treatment-related adverse events. These risks have led regulatory agencies to require specific monitoring for replication-competent viruses, both prior to and after treatment of patients with gene therapy products. Monitoring the risk of cell expansion and malignancy is also required. In this review, we discuss the rational potential approaches and challenges to meeting the US FDA expectations listed in current guidance documents.

Replication competent retrovirus testing (RCR) in the National Gene Vector Biorepository: No evidence of RCR in 1,595 post-treatment peripheral blood samples obtained from 60 clinical trials.

The clinical impact of any therapy requires the product be safe and effective. Gammaretroviral vectors pose several unique risks, including inadvertent exposure to replication competent retrovirus (RCR) that can arise during vector manufacture. The US FDA has required patient monitoring for RCR, and the National Gene Vector Biorepository is an NIH resource that has assisted eligible investigators in meeting this requirement. To date, we have found no evidence of RCR in 338 pre-treatment and 1,595 post-treatment blood samples from 737 patients associated with 60 clinical trials. Most samples (75%) were obtained within 1 year of treatment, and samples as far out as 9 years after treatment were analyzed. The majority of trials (93%) were cancer immunotherapy, and 90% of the trials used vector products produced with the PG13 packaging cell line. The data presented here provide further evidence that current manufacturing methods generate RCR-free products and support the overall safety profile of retroviral gene therapy.

Developing Palliative Medicine as an Accredited Medical Specialty in Kenya.

PURPOSE: Most people living with life-limiting illnesses in Kenya lack access to palliative care. Globally, palliative medicine is a growing specialty that equips clinicians with the training required to improve the quality of life for people living with a wide variety of serious illnesses. Optimal delivery relies on a skilled workforce with specialty-level training, and we identified the absence of board-accredited training programs for clinical officers (COs) and physicians as a barrier to providing high-quality palliative care in Kenya. METHODS: We held a series of stakeholder meetings with expert palliative care clinicians, leaders, and educators from Kenya and other countries to develop and implement a comprehensive, evidence-based palliative medicine curriculum for COs. RESULTS: We developed a higher diploma program that is being administered by the Moi Teaching and Referral Hospital College in Eldoret, Kenya, with faculty from Moi University School of Medicine and affiliated institutions. We have collaborated to create the first diploma awarding program in palliative medicine in Kenya. Our efforts have led the Kenyan CO Council adding palliative medicine to their list of recognized and licensed specialties. COs are now enrolled in an 18-month program that will lead to a higher diploma and national recognition as palliative care specialists. CONCLUSION: Early building of consensus and educating policymakers, regulatory bodies, and government personnel was an important step to overcome the challenge of palliative care misconceptions. The unique capacity of global partnerships and early and frequent stakeholder involvement is critical in novel program development. Local ownership of such in-country programs is key, and the stakeholders should be included in strategies for sustainability.

Gene therapy access: Global challenges, opportunities, and views from Brazil, South Africa, and India.

Gene and cell therapies for a variety of life-limiting illnesses are under investigation, and a small number of commercial products have successfully obtained regulatory approval. The cost of treatment is high, and clinical studies evaluating safety and efficacy are performed predominately in high-income countries. We reviewed the current status of gene and cell therapies in low- and middle-income countries and highlighted the need and current barriers to access. The state of product development in Brazil, South Africa, and India is discussed, including lessons learned from American Society of Gene and Cell Therapy (ASGCT)-sponsored virtual symposia in each of these countries.

Palliative Care Needs in Breast Cancer Patients Entering Inpatient Hospice in Western Kenya.

CONTEXT: Breast cancer in Kenya is associated with a high mortality due to late stage disease at presentation and limited access to specialty care. OBJECTIVES: To understand the symptom burden in breast cancer patients entering hospice in Western Kenya and utilize the data to meet the growing need for palliative care and hospice services. METHODS: We conducted a quality improvement exercise to assess the needs of Kenyan women admitted to inpatient hospice with the diagnosis of breast cancer. A retrospective chart review was undertaken to collect and collate demographic, physical and symptom data from a standardized admission form and the medical record. RESULTS: Between 2011-2019, 62 women with breast cancer were admitted for care. The median age was 50.0 years (range 23-86) and the median time from diagnosis to admission one year (range 0-4). Only 20% had received surgical treatment for breast cancer. Pain was the predominant symptom on admission (98%) and breast wounds were the most common physical finding. Approximately 50% voiced worry, depression, and stress with <10% voicing spiritual distress. The mean length of stay was 42.6 days (median 10, range 1-1185). While over 70% died in hospice, 27% were discharged home. CONCLUSIONS: The low rate of surgical intervention leads to painful breast wounds that were a major factor for many women seeking hospice admission. The findings challenge our team to maintain expertise in pain and wound management but to also include breast cancer awareness in our rural outreach services.

Electroceutical fabric lowers zeta potential and eradicates coronavirus infectivity upon contact.

Coronavirus with intact infectivity attached to PPE surfaces pose significant threat to the spread of COVID-19. We tested the hypothesis that an electroceutical fabric, generating weak potential difference of 0.5 V, disrupts the infectivity of coronavirus upon contact by destabilizing the electrokinetic properties of the virion. Porcine respiratory coronavirus AR310 particles (105) were placed in direct contact with the fabric for 1 or 5 min. Following one minute of contact, zeta potential of the porcine coronavirus was significantly lowered indicating destabilization of its electrokinetic properties. Size-distribution plot showed appearance of aggregation of the virus. Testing of the cytopathic effects of the virus showed eradication of infectivity as quantitatively assessed by PI-calcein and MTT cell viability tests. This work provides the rationale to consider the studied electroceutical fabric, or other materials with comparable property, as material of choice for the development of PPE in the fight against COVID-19.

Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency.

BACKGROUND: Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency. METHODS: We treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human ADA. Data from the two U.S. studies (in which fresh and cryopreserved formulations were used) at 24 months of follow-up were analyzed alongside data from the U.K. study (in which a fresh formulation was used) at 36 months of follow-up. RESULTS: Overall survival was 100% in all studies up to 24 and 36 months. Event-free survival (in the absence of reinitiation of enzyme-replacement therapy or rescue allogeneic hematopoietic stem-cell transplantation) was 97% (U.S. studies) and 100% (U.K. study) at 12 months; 97% and 95%, respectively, at 24 months; and 95% (U.K. study) at 36 months. Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. studies and in 19 of 20 patients in the U.K. study. Patients had sustained metabolic detoxification and normalization of ADA activity levels. Immune reconstitution was robust, with 90% of the patients in the U.S. studies and 100% of those in the U.K. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. Most adverse events were of low grade. CONCLUSIONS: Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained ADA expression, metabolic correction, and functional immune reconstitution. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01852071, NCT02999984, and NCT01380990.).

Long-term outcomes after gene therapy for adenosine deaminase severe combined immune deficiency.

Patients lacking functional adenosine deaminase activity have severe combined immunodeficiency (ADA SCID), which can be treated with ADA enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT), or autologous HSCT with gene-corrected cells (gene therapy [GT]). A cohort of 10 ADA SCID patients, aged 3 months to 15 years, underwent GT in a phase 2 clinical trial between 2009 and 2012. Autologous bone marrow CD34+ cells were transduced ex vivo with the MND (myeloproliferative sarcoma virus, negative control region deleted, dl587rev primer binding site)-ADA gammaretroviral vector (gRV) and infused following busulfan reduced-intensity conditioning. These patients were monitored in a long-term follow-up protocol over 8 to 11 years. Nine of 10 patients have sufficient immune reconstitution to protect against serious infections and have not needed to resume ERT or proceed to secondary allogeneic HSCT. ERT was restarted 6 months after GT in the oldest patient who had no evidence of benefit from GT. Four of 9 evaluable patients with the highest gene marking and B-cell numbers remain off immunoglobulin replacement therapy and responded to vaccines. There were broad ranges of responses in normalization of ADA enzyme activity and adenine metabolites in blood cells and levels of cellular and humoral immune reconstitution. Outcomes were generally better in younger patients and those receiving higher doses of gene-marked CD34+ cells. No patient experienced a leukoproliferative event after GT, despite persisting prominent clones with vector integrations adjacent to proto-oncogenes. These long-term findings demonstrate enduring efficacy of GT for ADA SCID but also highlight risks of genotoxicity with gRVs. This trial was registered at www.clinicaltrials.gov as #NCT00794508.

Use of a Novel Trigger Tool to Identify Palliative Care Needs in Surgical Patients at a National Referral Hospital in Kenya: A Pilot Study.

Background: Addressing unmet palliative care needs in high-risk surgical patients in low- and middle-income countries must include innovative approaches to limitations in personnel and culturally acceptable assessment modalities. Objectives: We assessed the utility of a novel seven-item "Step-1" trigger tool in identifying surgical patients who may benefit from palliative care. Design: All adult patients (≥18 years) on general surgery, neurosurgery, and orthopedic surgery wards were enrolled over a four-month period. Setting/Subjects: This study took place at Moi Teaching and Referral Hospital (MTRH), one of two Kenyan national referral hospitals. Measurements: The "Step-1" trigger tool was administered, capturing provider estimates of prognosis, cancer history, social barriers, admission frequency, hospice history, symptom burden, and functional decline/wasting. A cut-point of ≥3 positive factors was selected, indicating a patient may benefit from palliative care. Results: A total of 411 patients were included for analysis. Twenty-five percent (n = 102) of patients had scores ≥3. The cut-point of ≥3 was significantly associated with identifying high-risk patients (HRP; χ2 = 32.3, p < 0.01), defined as those who died or were palliatively discharged, with a sensitivity and specificity of 63.9% and 78.9%, respectively. Survey questions with the highest overall impact included: "Would you be not surprised if the patient died within 12 months?," "Are there uncontrolled symptoms?," and "Is there functional decline/wasting?" Conclusions: This pilot study demonstrates that the "Step-One" trigger tool is a simple and effective method to identify HRP in resource-limited settings. Although this study identified three highly effective questions, the seven-question assessment is flexible and can be adapted to different settings.

Transitioning from development to commercial: risk-based guidance for critical materials management in cell therapies.

A key hurdle to ensuring patient access to cell and gene therapies (CGTs) and continued growth of the industry is the management of raw materials. The combination of rapid growth, individual product and process complexity and limited industry-specific guidance or awareness presents non-obvious risk mitigation challenges for transitioning from development to clinical application. Understanding, assessing and mitigating the varied raw material risks for CGT products during product and clinical development are critical for ensuring smooth transitions into commercialization and for preventing interruption of product supply to patients. This article presents a risk-based approach driven by concerns for patient safety that can help focus and coordinate efforts to address the most critical risk factors. Highlighted are some of the highest risk materials common to the manufacture of many CGTs, including the primary starting material, culture media, reagents and single-use components. Using a hypothetical gene-edited cell therapy as an example, we describe the general manufacturing process and subsequently incorporate the described methodology to perform a sample risk assessment. The practical approach described herein is intended to assist CGT manufacturers and suppliers in actively assessing materials early in development to provide a basic starting point for mitigating risks experienced when translating CGT products for clinical and long-term commercial application.

The National Gene Vector Biorepository: Eleven Years of Providing Resources to the Gene Therapy Community.

The National Gene Vector Biorepository (NGVB) program has been highly accessed by gene therapy investigators. The reagent repository has distributed over 1,000 reagents to 397 investigators. The Pharmacology/Toxicology Archive contains over 36,000 specimens from a variety of adeno-associated virus (AAV), adenoviral, and other pharmacology/toxicology studies. NGVB also maintains a searchable database of gene therapy pharmacology/toxicology studies to promote data sharing. NGVB has provided Food and Drug Administration (FDA)-mandated replication-competent virus testing for over 70 clinical trials. From 2008 to 2018, there have been 114 publications acknowledging the NGVB. It is unlikely that any other National Institutes of Health (NIH)-funded program has served as many gene therapy investigators as the NGVB.

The Access Technology Program of the Indiana Clinical Translational Sciences Institute (CTSI): A model to facilitate access to cutting-edge technologies across a state.

INTRODUCTION: Access to cutting-edge technologies is essential for investigators to advance translational research. The Indiana Clinical and Translational Sciences Institute (CTSI) spans three major and preeminent universities, four large academic campuses across the state of Indiana, and is mandate to provide best practices to a whole state. METHODS: To address the need to facilitate the availability of innovative technologies to its investigators, the Indiana CTSI implemented the Access Technology Program (ATP). The activities of the ATP, or any program of the Indiana CTSI, are challenged to connect technologies and investigators on the multiple Indiana CTSI campuses by the geographical distances between campuses (1-4 hr driving time). RESULTS: Herein, we describe the initiatives developed by the ATP to increase the availability of state-of-the-art technologies to its investigators on all Indiana CTSI campuses, and the methods developed by the ATP to bridge the distance between campuses, technologies, and investigators for the advancement of clinical translational research. CONCLUSIONS: The methods and practices described in this publication may inform other approaches to enhance translational research, dissemination, and usage of innovative technologies by translational investigators, especially when distance or multi-campus cultural differences are factors to efficient application.

Replication-Competent Lentivirus Analysis of Vector-Transduced T Cell Products Used in Cancer Immunotherapy Clinical Trials.

Lentiviral vectors are being used in a growing number of clinical applications, including T cell immunotherapy for cancer. As this new technology moves forward, a safety concern is the inadvertent recombination and subsequent development of a replication-competent lentivirus (RCL) during the manufacture of the vector material. To assess this risk, regulators have required screening of T cell products infused into patients for RCL. Since vector particles have many of the proteins and nucleotide sequences found in RCL, a biologic assay has proven the most sensitive method for RCL detection. As regulators have required screening of up to 108 cells per T cell product, this method described a procedure for assessing RCL contamination of large-volume T cell products.

IND-Enabling Studies for a Clinical Trial to Genetically Program a Persistent Cancer-Targeted Immune System.

PURPOSE: To improve persistence of adoptively transferred T-cell receptor (TCR)-engineered T cells and durable clinical responses, we designed a clinical trial to transplant genetically-modified hematopoietic stem cells (HSCs) together with adoptive cell transfer of T cells both engineered to express an NY-ESO-1 TCR. Here, we report the preclinical studies performed to enable an investigational new drug (IND) application. EXPERIMENTAL DESIGN: HSCs transduced with a lentiviral vector expressing NY-ESO-1 TCR and the PET reporter/suicide gene HSV1-sr39TK and T cells transduced with a retroviral vector expressing NY-ESO-1 TCR were coadministered to myelodepleted HLA-A2/Kb mice within a formal Good Laboratory Practice (GLP)-compliant study to demonstrate safety, persistence, and HSC differentiation into all blood lineages. Non-GLP experiments included assessment of transgene immunogenicity and in vitro viral insertion safety studies. Furthermore, Good Manufacturing Practice (GMP)-compliant cell production qualification runs were performed to establish the manufacturing protocols for clinical use. RESULTS: TCR genetically modified and ex vivo-cultured HSCs differentiated into all blood subsets in vivo after HSC transplantation, and coadministration of TCR-transduced T cells did not result in increased toxicity. The expression of NY-ESO-1 TCR and sr39TK transgenes did not have a detrimental effect on gene-modified HSC's differentiation to all blood cell lineages. There was no evidence of genotoxicity induced by the lentiviral vector. GMP batches of clinical-grade transgenic cells produced during qualification runs had adequate stability and functionality. CONCLUSIONS: Coadministration of HSCs and T cells expressing an NY-ESO-1 TCR is safe in preclinical models. The results presented in this article led to the FDA approval of IND 17471.