Clinical Practice Recommendations for Hematopoietic Cell Transplantation and Cellular Therapies in Follicular Lymphoma: A Collaborative Effort on behalf of The American Society of Transplantation and Cellular Therapy and the European Society of Blood and Marrow Transplantation.

Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma (NHL), accounting for nearly one-third of all NHL. The therapeutic landscape for patients with FL has significantly expanded over the past decade, but the disease continues to be considered incurable. Hematopoietic cell transplantation (HCT) is potentially curative in some cases. Recently, the emergence of chimeric antigen receptor T-cell therapy (CAR-T) for patients with relapsed/refractory (R/R) FL has yielded impressive response rates and long-term remissions, but definitive statement on the curative potential of CAR-T is currently not possible due to limited patient numbers and relatively short follow up. A consensus on the contemporary role, optimal timing, and sequencing of HCT (autologous or allogeneic) and cellular therapies in FL is needed. As a result, the American Society of Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines endorsed this effort to formulate consensus recommendations to address this unmet need. The RAND-modified Delphi method was used to generate 15 consensus statements/recommendations. Of note, the use of bispecific antibodies in R/R FL was not in the scope of this project. Key statements/recommendations are as follows: 1) Autologous HCT is recommended as an option for consolidation therapy in patients with progression of untransformed disease within 24 months of front line chemoimmunotherapy and upon achieving a complete (CR) or partial response (PR) to salvage second line therapies; 2) CAR-T is considered as a treatment option for patients who did not achieve CR or PR after second or subsequent lines of therapies; 3) Allogeneic HCT is considered as consolidative treatment in relapsed FL patients with chemosensitive disease who have received 3 or more lines of systemic therapy and are the following clinical scenarios: post CAR-T failure; lack of access to CAR-T or have therapy related myeloid neoplasm. These clinical practice recommendations will help guide clinicians managing patients with FL.

A multi-institutional survey of apheresis services among institutions in the United States.

INTRODUCTION: Apheresis practices in the United States (US) have not been comprehensively characterized to date. This study aimed to address this gap by evaluating apheresis therapy through a national survey. METHODS: A multi-institutional survey was conducted between April and July 2023. The survey, comprising 54 questions, focused on institutional demographics, procedures, equipment, staffing, training, and impacts of the Coronavirus Disease 2019 (COVID-19) pandemic. Responses from 22 institutions, primarily academic medical centers, were analyzed. RESULTS: Therapeutic plasma exchange (TPE) was the most common procedure, followed by hematopoietic progenitor cell collection (HPC-A) and red blood cell exchange (RCE). CAR-T cell collections were widespread, with some institutions supporting over 30 protocols concurrently. Most sites used the Spectra Optia Apheresis System, were managed by a transfusion medicine service, and employed internal apheresis providers. Insufficient staffing levels, exacerbated by the COVID-19 pandemic, were common and most often addressed using overtime. DISCUSSION: The survey highlighted the ubiquity of TPE, expanding cellular collections and staffing challenges. The role of apheresis in supporting cellular therapy, particularly in newly developing cell and gene therapies and clinical trials, was evident. Staffing issues during the pandemic emphasized the need for innovative recruitment strategies. CONCLUSION: This nationwide survey provides the most comprehensive analysis to date of apheresis practices in large US academic centers.

Cellular Therapy in Experimental Autoimmune Encephalomyelitis as an Adjuvant Treatment to Translate for Multiple Sclerosis.

This study aims to evaluate and compare cellular therapy with human Wharton's jelly (WJ) mesenchymal stem cells (MSCs) and neural precursors (NPs) in experimental autoimmune encephalomyelitis (EAE), a preclinical model of Multiple Sclerosis. MSCs were isolated from WJ by an explant technique, differentiated to NPs, and characterized by cytometry and immunocytochemistry analysis after ethical approval. Forty-eight rats were EAE-induced by myelin basic protein and Freund's complete adjuvant. Forty-eight hours later, the animals received intraperitoneal injections of 250 ng/dose of Bordetella pertussis toxin. Fourteen days later, the animals were divided into the following groups: a. non-induced, induced: b. Sham, c. WJ-MSCs, d. NPs, and e. WJ-MSCs plus NPs. 1 × 105. Moreover, the cells were placed in a 10 µL solution and injected via a stereotaxic intracerebral ventricular injection. After ten days, the histopathological analysis for H&E, Luxol, interleukins, and CD4/CD8 was carried out. Statistical analyses demonstrated a higher frequency of clinical manifestation in the Sham group (15.66%) than in the other groups; less demyelination was seen in the treated groups than the Sham group (WJ-MSCs, p = 0.016; NPs, p = 0.010; WJ-MSCs + NPs, p = 0.000), and a lower cellular death rate was seen in the treated groups compared with the Sham group. A CD4/CD8 ratio of <1 showed no association with microglial activation (p = 0.366), astrocytes (p = 0.247), and cell death (p = 0.577) in WJ-MSCs. WJ-MSCs and NPs were immunomodulatory and neuroprotective in cellular therapy, which would be translated as an adjunct in demyelinating diseases.

CAR-NKT Cells in Asthma: Use of NKT as a Promising Cell for CAR Therapy.

NKT cells, unique lymphocytes bridging innate and adaptive immunity, offer significant potential for managing inflammatory disorders like asthma. Activating iNKT induces increasing IFN-γ, TGF-ß, IL-2, and IL-10 potentially suppressing allergic asthma. However, their immunomodulatory effects, including granzyme-perforin-mediated cytotoxicity, and expression of TIM-3 and TRAIL warrant careful consideration and targeted approaches. Although CAR-T cell therapy has achieved remarkable success in treating certain cancers, its limitations necessitate exploring alternative approaches. In this context, CAR-NKT cells emerge as a promising approach for overcoming these challenges, potentially achieving safer and more effective immunotherapies. Strategies involve targeting distinct IgE-receptors and their interactions with CAR-NKT cells, potentially disrupting allergen-mast cell/basophil interactions and preventing inflammatory cytokine release. Additionally, targeting immune checkpoints like PDL-2, inducible ICOS, FASL, CTLA-4, and CD137 or dectin-1 for fungal asthma could further modulate immune responses. Furthermore, artificial intelligence and machine learning hold immense promise for revolutionizing NKT cell-based asthma therapy. AI can optimize CAR-NKT cell functionalities, design personalized treatment strategies, and unlock a future of precise and effective care. This review discusses various approaches to enhancing CAR-NKT cell efficacy and longevity, along with the challenges and opportunities they present in the treatment of allergic asthma.

Nutritional Support Best Practices in Pediatric Blood and Marrow Transplant Patients: An Integrative Review.

Nutrition is vital to the long-term survival of children undergoing blood and marrow transplantation (BMT), but there is no standardization on how to optimize the nutritional status of these patients. A literature search was performed to evaluate nutritional support approaches currently in practice for pediatric patients who are undergoing BMT. CINAHL, Embase, and Cochrane databases were searched for peer-reviewed articles evaluating nutritional interventions for BMT recipients aged 20 or younger. Nine articles published between 2019 and 2023 were found and reviewed. The nutritional support varied between enteral nutrition, parenteral nutrition, a combination of both, and prophylactic feeding tube placement. The post-transplant outcomes identified as associated with alterations in nutritional regimens included length of stay, date of platelet engraftment, incidence of acute graft-versus-host disease, infection rate, and overall survival. The use of any amount of enteral nutrition compared to parenteral alone was beneficial. Complications during BMT can potentially be decreased via prioritizing enteral nutrition over parenteral. The paucity of literature on this topic highlights an unmet need in the field. Future research should focus on ways to optimize the nutritional support of transplant recipients, including increasing the likelihood of enteral feeding tube placement and utilization.

Lymphoma for the acute physician: diagnostic challenges and initial treatment decisions.

Prompt diagnosis of lymphoma facilitates early treatment and improves outcomes for patients. For non-haemato-oncologists, it is important to have an understanding of how lymphoma can present and the initial work-up. This review is intended to provide clinicians with background to aid clinical decisional making at presentation and when managing treatment related complications. There will be particular emphasis on emergency presentations (tumour lysis syndrome, management of patients with a mediastinal mass, infections in lymphoma patients) and novel treatment options which have unique toxicities often requiring multi-specialty expertise.

Long-term engraftment and maturation of autologous iPSC-derived cardiomyocytes in two rhesus macaques.

Cellular therapies with cardiomyocytes produced from induced pluripotent stem cells (iPSC-CMs) offer a potential route to cardiac regeneration as a treatment for chronic ischemic heart disease. Here, we report successful long-term engraftment and in vivo maturation of autologous iPSC-CMs in two rhesus macaques with small, subclinical chronic myocardial infarctions, all without immunosuppression. Longitudinal positron emission tomography imaging using the sodium/iodide symporter (NIS) reporter gene revealed stable grafts for over 6 and 12 months, with no teratoma formation. Histological analyses suggested capability of the transplanted iPSC-CMs to mature and integrate with endogenous myocardium, with no sign of immune cell infiltration or rejection. By contrast, allogeneic iPSC-CMs were rejected within 8 weeks of transplantation. This study provides the longest-term safety and maturation data to date in any large animal model, addresses concerns regarding neoantigen immunoreactivity of autologous iPSC therapies, and suggests that autologous iPSC-CMs would similarly engraft and mature in human hearts.

Essentials of CAR-T Therapy and Associated Microbial Challenges in Long Run Immunotherapy.

Chimeric antigen receptor (CAR)-T cell therapy has shown potential in improving outcomes for individuals with hematological malignancies. However, achieving long-term full remission for blood cancer remains challenging due to severe life-threatening toxicities such as limited anti-tumor efficacy, antigen escape, trafficking restrictions, and limited tumor invasion. Furthermore, the interactions between CAR-T cells and their host tumor microenvironments have a significant impact on CAR-T function. To overcome these considerable hurdles, fresh methodologies and approaches are needed to produce more powerful CAR-T cells with greater anti-tumor activity and less toxicity. Despite advances in CAR-T research, microbial resistance remains a significant obstacle. In this review, we discuss and describe the basics of CAR-T structures, generations, challenges, and potential risks of infections in CAR-T cell therapy.

Advances and challenges in regenerative therapies for abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a significant source of mortality worldwide and carries a mortality of greater than 80% after rupture. Despite extensive efforts to develop pharmacological treatments, there is currently no effective agent to prevent aneurysm growth and rupture. Current treatment paradigms only rely on the identification and surveillance of small aneurysms, prior to ultimate open surgical or endovascular repair. Recently, regenerative therapies have emerged as promising avenues to address the degenerative changes observed in AAA. This review briefly outlines current clinical management principles, characteristics, and pharmaceutical targets of AAA. Subsequently, a thorough discussion of regenerative approaches is provided. These include cellular approaches (vascular smooth muscle cells, endothelial cells, and mesenchymal stem cells) as well as the delivery of therapeutic molecules, gene therapies, and regenerative biomaterials. Lastly, additional barriers and considerations for clinical translation are provided. In conclusion, regenerative approaches hold significant promise for in situ reversal of tissue damages in AAA, necessitating sustained research and innovation to achieve successful and translatable therapies in a new era in AAA management.

Therapeutic Characteristics of Alveolar-like Macrophages in Mouse Models of Hyperoxia and LPS-Induced Lung Inflammation.

Acute respiratory distress syndrome (ARDS) is a severe lung disease of high mortality (30-50%). Patients require lifesaving supplemental oxygen therapy; however, hyperoxia can induce pulmonary inflammation and cellular damage. Although alveolar macrophages (AMs) are essential for lung immune homeostasis, they become compromised during inflammatory lung injury. To combat this, stem cell-derived alveolar-like macrophages (ALMs) are a prospective therapeutic for lung diseases like ARDS. Using in vitro and in vivo approaches, we investigated the impact of hyperoxia on murine ALMs during acute inflammation. In vitro, ALMs retained their viability, growth and antimicrobial abilities when cultured at 60% O2,while they die at 90% O2. In contrast, ALMs instilled in mouse lungs remained viable during exposure of mice to 90% O2. The ability of the delivered ALMs to phagocytose Pseudomonas aeruginosa was not impaired by exposure to 60 or 90% O2. Furthermore, ALMs remained immunologically stable in a murine model of LPS-induced lung inflammation when exposed to 60 and 90% O2 and effectively attenuated the accumulation of CD11b+ inflammatory cells in the airways. These results support the potential use of ALMs in ARDS patients receiving supplemental oxygen therapy.

Facilitating the ethical sourcing of donor hematopoietic stem cells for cell and gene therapy research and development.

Aim: Unrelated stem cell donor registries (DRs) are increasingly engaging in the field of cell and gene therapy (CGT). This study aims to explore the values, concerns, needs and expectations of donors and members of the public on donating hematopoietic stem cells (HSCs) for CGT. Methods: Seven focus groups were conducted in 2019 with members of the public, prospective donors and donors on the Anthony Nolan DR in the UK. Results: Participants expressed concerns over increased frequency of donation and incidental findings and required more information on the type of research including the purpose and possible outcomes. Conclusion: Addressing donors' concerns, needs and expectations on donating cellular materials for CGT research and development is essential to maintaining the highest standards for donor care and safety within this rapidly emerging field.

This study aims to explore the values, concerns, needs and expectations of people who donate, or consider donating, their stem cells (cells that can develop into many different types of cells) for research that could lead to new medical treatments. We focused on the thoughts of these donors about providing their cells for use in cell and gene therapy (CGT) research, a field that is rapidly advancing but still forming its rules and ethical guidelines. In 2019, we conducted seven focus groups (FGs) with a total of 73 people in the UK. This included individuals who are registered as potential stem cell donors on the Anthony Nolan unrelated stem cell donor register (DR), those who have already donated stem cells and members of the general public. We explored their thoughts about their donated cells being used for research to develop new therapies rather than for direct treatment of patients. Questions during the FGs touched on topics such as the roles of various organizations in managing donated cells, the commercial use of these cells and where responsibilities lie in ensuring ethical practices. Participants expressed a strong desire for openness and clear communication regarding how their donated cells are used in research. They wanted to ensure that any use of their cells aligns with their personal values and the ethical standards of the organizations handling the donations. Participants expected DRs like Anthony Nolan to safeguard their interests and the ethical use of their cells. This study highlights that while donors are generally willing to contribute to advancements in CGT research, they need clear, understandable information about how their donations are used. This is crucial for maintaining their trust and willingness to donate. Overall, this study underscores the importance of ethical practices and donor engagement in the growing field of CGT, ensuring that donor contributions are respected and used responsibly.

Future directions in haploidentical hematopoietic stem cell transplantation.

Outcomes of haploidentical hematopoietic stem cell transplantation (haplo-SCT) have improved over time. Graft failure and graft-versus-host disease (GVHD), which were important complications in major human leukocyte antigen (HLA)-disparity stem cell transplantation, have significantly decreased. These improvements have led to an exponential increase in the use of haploidentical donors for transplantation, as well as in the number of publications evaluating haplo-SCT outcomes. Many studies focused on factors important in donor selection, novel conditioning regimens or GVHD prophylaxis, the impact of donor-specific anti-HLA antibodies (DSA), as well as strategies to prevent disease relapse post-transplant. DSA represents an important limitation and multimodality desensitization protocols, including plasma exchange, rituximab, intravenous immunoglobulin and donor buffy coat infusion, can contribute to the successful engraftment in patients with high DSA levels and is currently the standard therapy for highly allosensitized individuals. With regards to donor selection, younger donors are preferred due to lower risk of complications and better transplant outcomes. Moreover, recent studies also showed that younger haploidentical donors may be a better choice than older-matched unrelated donors. Improvement of disease relapse remains a top priority, and several studies have demonstrated that higher natural killer (NK) cell numbers early post-transplant are associated with improved outcomes. Prospective studies have started to assess the role of NK cell administration in decreasing post-transplant relapse. These studies suggest that the incorporation of other cell products post-transplant, including the administration of chimeric antigen receptor T-cells, should be explored in the future.

Modifying the Secretome of Mesenchymal Stem Cells Prolongs the Regenerative Treatment Window for Encephalopathy of Prematurity.

Clinical treatment options to combat Encephalopathy of Prematurity (EoP) are still lacking. We, and others, have proposed (intranasal) mesenchymal stem cells (MSCs) as a potent therapeutic strategy to boost white matter repair in the injured preterm brain. Using a double-hit mouse model of diffuse white matter injury, we previously showed that the efficacy of MSC treatment was time dependent, with a significant decrease in functional and histological improvements after the postponement of cell administration. In this follow-up study, we aimed to investigate the mechanisms underlying this loss of therapeutic efficacy. Additionally, we optimized the regenerative potential of MSCs by means of genetic engineering with the transient hypersecretion of beneficial factors, in order to prolong the treatment window. Though the cerebral expression of known chemoattractants was stable over time, the migration of MSCs to the injured brain was partially impaired. Moreover, using a primary oligodendrocyte (OL) culture, we showed that the rescue of injured OLs was reduced after delayed MSC coculture. Cocultures of modified MSCs, hypersecreting IGF1, LIF, IL11, or IL10, with primary microglia and OLs, revealed a superior treatment efficacy over naïve MSCs. Additionally, we showed that the delayed intranasal administration of IGF1-, LIF-, or IL11-hypersecreting MSCs, improved myelination and the functional outcome in EoP mice. In conclusion, the impaired migration and regenerative capacity of intranasally applied MSCs likely underlie the observed loss of efficacy after delayed treatment. The intranasal administration of IGF1-, LIF-, or IL11-hypersecreting MSCs, is a promising optimization strategy to prolong the window for effective MSC treatment in preterm infants with EoP.

Cellular therapies for bone repair: current insights.

Mesenchymal stem cells are core to bone homeostasis and repair. They both provide the progenitor cells from which bone cells are formed and regulate the local cytokine environment to create a pro-osteogenic environment. Dysregulation of these cells is often seen in orthopaedic pathology and can be manipulated by the physician treating the patient. This narrative review aims to describe the common applications of cell therapies to bone healing whilst also suggesting the future direction of these techniques.

Human Stem Cells in Regenerative Medicine.

Modern medicine now has the capacity to improve therapy for many human diseases by introducing adult somatic stem cells that can repair or replace defective or damaged tissues. However, the area is still in an early phase of development, so all new applications must be carefully designed for maximal safety as well as effectiveness.

Final outcomes analysis of the cell product SQZ-PBMC-HPV Phase 1 trial in incurable HPV16+ solid tumors shows improved overall survival in patients with increased CD8+ T cell tumor infiltration.

Cancer vaccines strive to induce robust, antigen-targeted, T-cell-mediated immune responses but have struggled to produce meaningful regression in solid tumors. An autologous cell vaccine, SQZ-PBMC-HPV, was developed by SQZ Biotechnologies using microfluidic squeezing technology to load PBMCs with HPV16 E6 and E7 antigens in HLA-A*02+ patients. The SQZ-PBMC-HPV-101 Phase 1 trial (NCT04084951) enrolled patients with incurable HPV16+ cancers. Here, we present a post hoc analysis of the relationship between Posttreatment CD8+ T cell infiltration and patient outcomes. SQZ-PBMC-HPV was administered as monotherapy every 3 weeks. Tumor samples were collected pre-dose and post-dose 4 weeks after treatment start. Biomarkers including CD8, MHC-I, E6, E7, GZMB, and Ki67 were evaluated by immunohistochemistry, immunofluorescence, and RNA in situ hybridization, and were correlated with clinical response, survival, and drug product composition. Eighteen patients had paired pre- and post-dose biopsies. Six (33%) had an increase in CD8+ T cell density in tumor parenchyma between screening and C2D8. Patients with increased CD8+ T cell density had improved disease control rate (66.7% vs 16.7%) and median overall survival (606.5 days vs 170.0 days, p = 0.0078). Drug product was significantly enriched for higher T cells and lower monocytes in the increased CD8+ T cell density group. In patients with incurable HPV16+ solid tumors treated with SQZ-PBMC-HPV, an increase in CD8+ T cell density within the tumor parenchyma was associated with superior disease control rate and overall survival. The product composition for patients with increased CD8+ T cell density was enriched for T cells.

Highlight of 2023: CAR T cells driving precision therapy for autoimmune disease.

CAR T cell therapy is showing remarkable results in autoimmune disease with treatment-refractory patients showing durable drug-free remission. Here, we highlight five key papers from 2023 that are driving the development of CAR T cells to improve precision, safety, efficacy and accessibility for the treatment of autoantibody-associated autoimmune diseases.

Anti-inflammatory and immunomodulatory effects of mesenchymal stem cell therapy on parasitic drug resistance.

INTRODUCTION: The emergence of antiparasitic drug resistance poses a concerning threat to animals and humans. Mesenchymal Stem Cells (MSCs) have been widely used to treat infections in humans, pets, and livestock. Although this is an emerging field of study, the current review outlines possible mechanisms and examines potential synergism in combination therapies and the possible harmful effects of such an approach. AREAS COVERED: The present study delved into the latest pre-clinical research on utilizing MSCs to treat parasitic infections. As per investigations, the introduction of MSCs to patients grappling with parasitic diseases like schistosomiasis, malaria, cystic echinococcosis, toxoplasmosis, leishmaniasis, and trypanosomiasis has shown a reduction in parasite prevalence. This intervention also alters the levels of both pro- and anti-inflammatory cytokines. Furthermore, the combined administration of MSCs and antiparasitic drugs has demonstrated enhanced efficacy in combating parasites and modulating the immune response. EXPERT OPINION: Mesenchymal stem cells are a potential solution for addressing parasitic drug resistance. This is mainly because of their remarkable immunomodulatory abilities, which can potentially help combat parasites' resistance to drugs.

Chimeric Cell Therapies as a Novel Approach for Duchenne Muscular Dystrophy (DMD) and Muscle Regeneration.

Chimerism-based strategies represent a pioneering concept which has led to groundbreaking advancements in regenerative medicine and transplantation. This new approach offers therapeutic potential for the treatment of various diseases, including inherited disorders. The ongoing studies on chimeric cells prompted the development of Dystrophin-Expressing Chimeric (DEC) cells which were introduced as a potential therapy for Duchenne Muscular Dystrophy (DMD). DMD is a genetic condition that leads to premature death in adolescent boys and remains incurable with current methods. DEC therapy, created via the fusion of human myoblasts derived from normal and DMD-affected donors, has proven to be safe and efficacious when tested in experimental models of DMD after systemic-intraosseous administration. These studies confirmed increased dystrophin expression, which correlated with functional and morphological improvements in DMD-affected muscles, including cardiac, respiratory, and skeletal muscles. Furthermore, the application of DEC therapy in a clinical study confirmed its long-term safety and efficacy in DMD patients. This review summarizes the development of chimeric cell technology tested in preclinical models and clinical studies, highlighting the potential of DEC therapy in muscle regeneration and repair, and introduces chimeric cell-based therapies as a promising, novel approach for muscle regeneration and the treatment of DMD and other neuromuscular disorders.

Evaluation of Methods to Obtain Peripheral Blood Mononuclear Cells From Deceased Donors for Tolerance-Induction Protocols.

Regulatory cell therapies have shown promise in tolerance-induction protocols in living donor organ transplantation. These protocols should be pursued in deceased donor transplantation. Donor peripheral mononuclear cells (PBMCs) are an optimal source of donor antigens for the induction of donor-specific regulatory cells. During the development of a regulatory cell tolerance-induction protocol with organs from deceased donors, we compared 3 methods of obtaining PBMCs from deceased donors focusing on cell yield, viability, and contamination of unwanted cell types. PBMC procurement methods: 1. During organ procurement at the time of cold perfusion, blood was collected from the vena cava and placed into a 10-liter blood collection bag, and thereafter transported to Karolinska University Hospital, where leukapheresis was performed (BCL). 2. Blood was collected via the vena cava into blood donation bags before cold perfusion. The bags underwent buffy coat separation and thereafter automated leukocyte isolation system (BCS). 3. To collect PBMCs, leukapheresis was performed via a central dialysis catheter on deceased donors in the intensive care unit (ICU) prior to the organ procurement procedure (LEU).All 3 methods to obtain PBMC from deceased donors were safe and did not affect the procurement of organs. BCL contained around 50% of NK cells in lymphocytes population. LEU had a highest yield of donor PBMC among 3 groups. LEU had the lower amount of granulocyte contamination, compared to BCS and BCL. Based on these results, we choose LEU as the preferred method to obtain donor PBMC in the development of our tolerance-induction protocol.