Natural killer (NK)-cell recognition and function against NK-resistant cancers remain substantial barriers to the broad application of NK-cell immunotherapy. Potential solutions include bispecific ...engagers that target NK-cell activity via an NK-activating receptor when simultaneously targeting a tumor-specific antigen, as well as enhancing functionality using IL12/15/18 cytokine pre-activation.
We assessed single-cell NK-cell responses stimulated by the tetravalent bispecific antibody AFM13 that binds CD30 on leukemia/lymphoma targets and CD16A on various types of NK cells using mass cytometry and cytotoxicity assays. The combination of AFM13 and IL12/15/18 pre-activation of blood and cord blood-derived NK cells was investigated
and
.
We found heterogeneity within AFM13-directed conventional blood NK cell (cNK) responses, as well as consistent AFM13-directed polyfunctional activation of mature NK cells across donors. NK-cell source also impacted the AFM13 response, with cNK cells from healthy donors exhibiting superior responses to those from patients with Hodgkin lymphoma. IL12/15/18-induced memory-like NK cells from peripheral blood exhibited enhanced killing of CD30
lymphoma targets directed by AFM13, compared with cNK cells. Cord-blood NK cells preactivated with IL12/15/18 and
expanded with K562-based feeders also exhibited enhanced killing with AFM13 stimulation via upregulation of signaling pathways related to NK-cell effector function. AFM13-NK complex cells exhibited enhanced responses to CD30
lymphomas
and
.
We identify AFM13 as a promising combination with cytokine-activated adult blood or cord-blood NK cells to treat CD30
hematologic malignancies, warranting clinical trials with these novel combinations.
Novel therapeutic options for cancer offer hope for patients and their families, particularly when the cancer has not responded to established treatment regimens. The CAR‐T cell therapeutic approach ...has changed the treatment paradigm for relapsed or refractory lymphoma, extending the capacity of the patient's own T cells to detect and eliminate cancer cells through genetic modification of T‐cell surface receptors. The process of establishing treatment centers and developing clinical expertize in this novel treatment strategy is complex. Time, resources, and a commitment to focusing health budgets on a new area are required. Currently, Singapore is the only country in southeast and south Asia with market authorization of the CAR‐T product, tisagenlecleucel. Availability of CAR‐T treatment across international borders provides patients in neighboring countries with choice in therapeutic options. This paper describes the unique hub‐and‐spoke cross‐border collaboration developed between Singapore and its neighbors to provide access to CAR‐T cell therapy for patients with relapsed or refractory lymphoma. To date in 2022, four patients have been included in the CAR‐T treatment cross‐border collaboration. Their stay in Singapore has been at least 2 months' duration, including the pre‐treatment evaluation, apheresis, CAR‐T cell infusion and post‐treatment monitoring. Patient support from referring and treating physicians, critical to the success of the undertaking, is characterized by early communication, patient selection, multi‐disciplinary care, post‐treatment monitoring, and attention to detail. The patient journey and the development and implementation of this unique collaboration are discussed.
Introduction
A high incidence of mortality and severe COVID‐19 infection was reported in hematopoietic stem cell transplant (HSCT) recipients during the early phases of the COVID‐19 pandemic; ...however, outcomes with subsequent severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants, such as the omicron variant, have yet to be reported. Additionally, rollout of COVID‐19 vaccinations in subsequent pandemic waves may modify COVID‐19 disease severity and mortality in this immunocompromised population. We describe COVID‐19 outcomes among a highly vaccinated population of HSCT recipients at a single center during successive waves of community transmission arising from the SARS‐CoV‐2 delta and omicron variants.
Methods
We retrospectively reviewed medical records of all HSCT recipients at our institution who tested positive for SARS‐CoV‐2 from May 2021 to May 2022. Descriptive statistics were reported; the chi‐square test was utilized to identify factors associated with 90‐day all‐cause mortality and severity of COVID‐19 infection.
Results
Over the 1‐year study period, 77 HSCT recipients at our center contracted COVID‐19 (43 allogenic; 34 autologous). Twenty‐six (33.8%) patients were infected with the SARS‐CoV‐2 delta variant, while 51 (66.2%) had the SARS‐CoV‐2 omicron variant. Thirty‐nine (50.6%) patients required hospitalization. More than 80% had received prior COVID‐19 vaccination (57.1% with two doses, 27.3% with three doses). The majority (90.9%) had mild disease; only one (1.3%) patient required mechanical ventilation. Active hematological disease at time of COVID‐19 infection was associated with increased odds of mortality odds ratio (OR) = 6.90, 95% confidence interval (CI) = 1.20–40. The 90‐day all‐cause mortality was 7.8% (six patients). Infection with the omicron variant (vs. delta) was associated with less severe illness (OR = 0.05, 95% CI = 0.01–0.47) and decreased odds of mortality (OR = 0.08, 95% CI = 0.01–0.76). Being on immunosuppression (OR = 5.10, 95% CI = 1.10–23.60) and being unvaccinated at disease onset (OR = 14.76, 95% CI = 2.89–75.4) were associated with greater severity of COVID‐19 infection.
Conclusion
We observed favorable outcomes with COVID‐19 infection in a cohort of vaccinated HSCT patients. The SARS‐CoV‐2 omicron variant was associated with both less severe illness and decreased odds of mortality. As COVID‐19 moves toward endemicity, early access to treatment and encouraging vaccination uptake is crucial in mitigating the challenge of COVID‐19 management among HSCT recipients. Surveillance and assessment of clinical outcomes with new SARS‐CoV‐2 variants also remains important in this immunocompromised population.
Chimeric antigen receptor (CAR) T cell therapy has ushered in a new era in cancer treatment. Remarkable outcomes have been demonstrated in patients with previously untreatable relapsed/refractory ...hematological malignancies. However, optimizing efficacy and reducing the risk of toxicities have posed major challenges, limiting the success of this therapy. The tumor microenvironment (TME) plays an important role in CAR T cell therapy’s effectiveness and the risk of toxicities. Increasing research studies have also identified various biomarkers that can predict its effectiveness and risk of toxicities. In this review, we discuss the various aspects of the TME and biomarkers that have been implicated thus far and discuss the role of creating scoring systems that can aid in further refining clinical applications of CAR T cell therapy and establishing a safe and efficacious personalised medicine for individuals.
BackgroundChimeric antigen receptor (CAR) T cell therapy has achieved successful remissions in relapsed/refractory B-cell leukemia and B-cell lymphomas in recent years.1 However, the observed ...heterogeneity in therapeutic responses underscoring immune monitoring in peripheral blood to provide insight into mechanisms, and potentially identify predictive markers.2 Notably, Asian populations have been largely underrepresented in CAR-T cell therapy trials.3 This study, conducting with longitudinal immunomonitoring of the aims to discover predictive biomarkers for the response to CAR-T cell therapy.MethodsBlood samples were collected from patients with B-ALL or lymphoma that received anti-CD19 CAR-T therapy in Singapore General Hospital. A comprehensive immunophenotyping was employed for both responders (R=5) and non-responders (NR=3) using a 33-plex flow cytometry panel. Dimension reduction was performed to obtain clusters of interest, which were then manually gated for statistical analysis.ResultsOur analyses uncovered distinct immune cell clusters with significant differences between the responder (R) and non-responder (NR) groups within the first three months following CAR-T cell infusion. At 1-month timepoint, a reduced frequency of CD16+ dendritic cells and increased proportion of γδ T cells, especially CD38+γδ T cells were associated with response. At 2-month timepoint, CD38+ NK and CD38+γδ T cells were found significantly enriched in R group. At 3-month timepoint, a successful response was correlated with a high presence of CD4+ central memory T cells and a reduced frequency of CD39+ Tregs. Further meta-clustering analysis revealed a trend towards elevated CD38 expression in CD3+, CD4+, CD8+, γδ T and CD45+ clusters in R group during the first 2 months as well as decreased CD39 expression in Tregs in R group over 3 months.ConclusionsCollectively, these results revealed the distinctly dynamic reconstruction of immune cells during the first 3 months following CAR-T infusion and identified the predictive values of CD38+ immune clusters in Asian patients. Ongoing works include analysing all time points and expanding to other modalities such as cytokines, proteomics and AI.ReferencesSterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. Apr 6 2021;11(4):69.Qi T, McGrath K, Ranganathan R, Dotti G, Cao Y. Cellular kinetics: A clinical and computational review of CAR-T cell pharmacology. Adv Drug Deliv Rev. Sep 2022;188:114421.Gajra A, Zalenski A, Sannareddy A, Jeune-Smith Y, Kapinos K, Kansagra A. Barriers to Chimeric Antigen Receptor T-Cell (CAR-T) Therapies in Clinical Practice. Pharmaceut Med. Jun 2022;36(3):163–171.Ethics ApprovalThe Centralized Institutional Review Board of SingHealth provided ethical approval for the use of patient materials in this study (CIRB ref.: 2022/2322; iSHaRe Ref. No. 202203–00014). Written informed consent is not required for deidentified subjects in Singapore.
Although chimeric antigen receptor (CAR) T‐cell therapy has demonstrated remarkable efficacy in patients with chemo‐refractory B‐cell lymphoma, a significant portion is refractory or relapse. ...Resistance is a major barrier to improving treatment efficacy and long‐term survival in CAR T‐cell therapy, and clinicians have very limited tools to discriminate a priori patients who will or will not respond to treatment. While CD19‐negative relapses due to loss of target antigen is well described, it accounts for only about 30% of cases with treatment failure. Recent efforts have shed light on mechanisms of CD19‐positive relapse due to tumor intrinsic resistance, T‐cell quality/manufacturing, or CAR T‐cell exhaustion mediated by hostile tumor microenvironment. Here, we review the latest updates of preclinical and clinical trials to investigate the mechanisms of resistance and relapse post CAR T‐cell therapy in B cell lymphoma and discuss novel treatment strategies to overcome resistance as well as advances that are useful for a CAR T therapist to optimize and personalize CAR T‐cell therapy.
The exciting advancement in cell therapies in both cancer and regenerative medicine provides alternative therapeutic opportunities for patients with advanced diseases who have exhausted all treatment ...options. However, with the emergence of new technologies and innovations this also brings about “unproven” cell‐ and tissue‐based interventions that have not been fully evaluated in clinical trials. Such interventions have resulted in injuries and deaths in patients. Collectively, these practices increase the potential for patient exploitation and harm through the imposition of medical and financial risks. Recognizing this worrying situation, in April 2020, European Medicine Agency (EMA), committee for Advances Therapies advised patients and the general public to be cautious unproven cell‐based therapies. Likewise, the Food and Drug Administration (FDA) has posted information about products marketed as stem cells, mesenchymal stromal cells (MSCs) or other regenerative medicine products, including the conditions for which they are approved, and which products are not approved. Though both EMA and FDA recognize the promise of cell‐based therapies for treating patients with serious diseases, both concur that well‐designed clinical trials and regulatory oversight are necessary to ensure safety, efficacy and quality of the therapies. In this review, I will mention proven cell therapies in the haematopoietic stem cell transplant setting and in the form of chimeric antigen receptor (CAR) T‐cell therapies and briefly mention how these therapies have evolved over time, the learning curve and scientific progress in these therapies. I will then mention briefly about MSCs and focus on both the proven and unproven aspects of MSC.
Current parenteral coronavirus disease 2019 (Covid-19) vaccines inadequately protect against infection of the upper respiratory tract. Additionally, antibodies generated by wild type (WT) spike-based ...vaccines poorly neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. To address the need for a second-generation vaccine, we have initiated a preclinical program to produce and evaluate a potential candidate. Our vaccine consists of recombinant Beta spike protein coadministered with synthetic CpG adjuvant. Both components are encapsulated within artificial cell membrane (ACM) polymersomes, synthetic nanovesicles efficiently internalized by antigen presenting cells, including dendritic cells, enabling targeted delivery of cargo for enhanced immune responses. ACM vaccine is immunogenic in C57BL/6 mice and Golden Syrian hamsters, evoking high serum IgG and neutralizing responses. Compared to an ACM-WT spike vaccine that generates predominantly WT-neutralizing antibodies, the ACM-Beta spike vaccine induces antibodies that neutralize WT and Beta viruses equally. Intramuscular (IM)-immunized hamsters are strongly protected from weight loss and other clinical symptoms after the Beta challenge but show delayed viral clearance in the upper airway. With intranasal (IN) immunization, however, neutralizing antibodies are generated in the upper airway concomitant with rapid and potent reduction of viral load. Moreover, antibodies are cross-neutralizing and show good activity against Omicron. Safety is evaluated in New Zealand white rabbits in a repeated dose toxicological study under Good Laboratory Practice (GLP) conditions. Three doses, IM or IN, at two-week intervals do not induce an adverse effect or systemic toxicity. Cumulatively, these results support the application for a Phase 1 clinical trial of ACM-polymersome-based Covid-19 vaccine (ClinicalTrials.gov identifier: NCT05385991).
Introduction
To profile conjunctival T cell populations in allogeneic hematopoietic stem cell transplant (HSCT) patients after instillation of daily topical cyclosporine-A (CsA) 0.1% cationic ...emulsion (Ikervis), and to evaluate patients’ tolerance to these eye drops.
Methods
Nineteen participants were prescribed Ikervis prophylaxis once daily to both eyes from 3–5 weeks pre-HSCT to 12 months post-HSCT. The outcome measure was conjunctival T cell proportions from flow cytometry after impression cytology. Covariates included visual acuity, intraocular pressure, slit lamp and fundal examination, dry eye (SPEED) and quality of life questionnaires, non-invasive keratograph tear break-up time (NIKBUT), conjunctival redness, meibography, lipid thickness, Schirmer test, tear cytokines, fluorescein staining, tear osmolarity, and meibomian gland expressibility.
Results
The conjunctival T cell analysis showed either stable or decreased proportions of conjunctival CD4 T cells at the last visit from baseline in compliant patients. CD4 proportions were increased in non-compliant patients and in the single patient who developed ocular graft-versus-host disease (GVHD). All patients were tolerant to Ikervis but 6/19 were not compliant. In the majority of patients, vision did not affect activities of daily living. Pre- and post-HSCT up to the last study visit, there was no statistically significant change in clinical covariates. Only one participant developed ocular GVHD at 9 months post-HSCT.
Conclusion
Superficial conjunctival T cell profile reflects compliance to daily topical Ikervis eye drops and clinical ocular surface parameters in allogenic HSCT patients. Tolerance is comparable to other formulations of topical CsA in the first 12 months.
ClinicalTrials.gov Identifier
NCT04636918. URL:
https://clinicaltrials.gov/ct2/show/NCT04636918?cond=ocular+Graft+Versus+Host+Disease&cntry=SG&draw=2&rank=2
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