Sodium stibogluconate and CD47-SIRPα blockade overcome resistance of anti-CD20-opsonized B cells to neutrophil killing

Anti-CD20 antibodies, like rituximab, are broadly used to treat B cell malignancies. These antibodies can induce various effector functions, including immune cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Neutrophils can induce ADCC towards solid cancer cells by trogoptosis, a cytotoxic mechanism known to be dependent on trogocytosis. However, neutrophils appear incapable of killing rituximab-opsonized B lymphoma cells. Nevertheless, neutrophils do trogocytose rituximab-opsonized B lymphoma cells, yet this only reduces CD20 surface expression, and is thought to render tumor cells therapeutically resistant to further rituximab-dependent destruction. Here, we demonstrate that resistance of B lymphoma cells towards neutrophil killing can be overcome by a combination of CD47-SIRPα checkpoint blockade and sodium stibogluconate (SSG), an anti-leishmanial drug and documented inhibitor of the tyrosine phosphatase SHP-1. SSG enhanced neutrophil-mediated ADCC of solid tumor cells, but enabled B lymphoma cell trogoptotic killing, by turning trogocytosis from a resistance-contributing mechanism into a cytotoxic anti-cancer one. The killing in the presence of SSG required both antibody opsonization of the target cells, as well as disruption of CD47-SIRPα interactions. These results provide a more detailed understanding of the role of neutrophil trogocytosis in antibody-mediated destruction of B cells and clues on how to further optimize antibody therapy of B cell malignancies.

Assessment of serum amylase, lipase and associated factors among patients with visceral leishmaniasis treated with sodium stibogluconate/paromomycin at University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia

Background Visceral leishmaniasis (VL) is a life-threatening parasitic disease next to malaria, which is responsible for the death of 50,000 patients annually. It has three major clinical stages, including visceral, cutaneous, and mucocutaneous leishmaniasis. Ethiopia is one of the east African countries commonly affected with leishmanisis disease. There are many drugs for leishmaniasis, including sodium stibogluconate and paromomycin combined therapy. However, the adverse effect of those combined drugs is not well-defined. Therefore, the purpose of this study was to assess serum amylase, lipase, and associated factors among patients with VL treatment with those combined drugs. Methods Hospital-based cross-sectional study was conducted at the University of Gondar Comprehensive Specialized Hospital Leishmaniasis Research and Treatment Center from February to September 2020 G.C. Simple random sampling technique was utilized to select study participants. The study participants who fulfill the inclusion criteria were included in the study with written informed consent. 5 ml of blood was withdrawn by an experienced health professional to analyze serum amylase and lipase level. Descriptive data was presented by tables, charts and graphs. Data was cleared, entered by Epi-data version 3.1 then transfer to STATA 14.1 SE version and for analysis paired t-test was used, for factors correlation and regression was used. Those factor variable who have p-value <0.25 was filtered and goes to multivariate regression and p-value <0.05 was considered as significant variables. Results The result of this study showed that there was a significant mean difference between serum pancreatic amylase and lipase before and after treatment. The mean ± SD level of serum amylase after treatment showed a statistically significant elevation (P<0.001) as compared to its level before treatment. Similarly, the mean ± SD level of serum lipase after treatment showed a statistically significant elevation (P<0.001) as compared to its level before treatment. There was also significant association between age and baseline serum amylase as compared to serum amylase after treatment. Similarly, there was also significant relation of age and serum lipase with serum lipase after treatment. Conclusion In this study, the level of serum amylase and lipase at treatment of cure was higher and there was an increase in mean serum amylase and lipase after a patient taking sodium stibogluconate and paromomycin combined drugs. Consequently, the elevated result of these biochemical profiles mainly associated with drug induced adverse effect and associated risk factors in VL patients.

Efficacy and safety of a combined treatment of sodium stibogluconate at 20mg/kg/day with upper maximum daily dose limit of 850mg and Paromomycin 15mg/kg/day in HIV negative visceral leishmaniasis patients. A retrospective study, northwest Ethiopia

Background Visceral leishmaniasis (VL) is one of the most neglected tropical infectious diseases. It is fatal if left untreated. The objective of this study was to assess the efficacy and safety of 17-day injections of combined regimen of sodium stibogluconate and paromomycin (SSG/PM) in HIV-negative VL patients. Methods A retrospective analysis of medical records of VL patients treated in the University of Gondar Hospital during period 2012–2019 was carried out. Results A total of 2836 patients were treated for VL from 2012 to 2019. Of these 1233 were treated with SSG-PM, and 1000 of them were included in the study. Initial cure was achieved in 922 (92.2%) patients. The frequency of treatment failure, treatment interruptions, default and deaths respectively were 30 (3%), 20 (2%), 13 (1.3%) and 15 (1.5%). Among 280 patients who completed 6-month follow up, the final cure was 93.9% (263/280), 4 (1.4%) relapsed and 13 (4.6%) developed post-kala-azar dermal leishmaniasis (PKDL). The most common adverse events (AEs) were raised liver transaminases (35.1%; 351 patients), injection site pain (29.1%, 291 patients) and raised serum alpha-amylase (29.1%, 291 patients). Factors associated with poor treatment outcomes were sepsis, pneumonia, and adverse events. Conclusion A combination of SSG at 20mg/kg with upper daily maximum dose of 850mg and PM was effective for achieving initial cure at end of treatment and safe for treatment of HIV negative VL patients in northwestern Ethiopia. Our data are consistent with previous reports and confirms effectiveness of SSG/PM treatment regimen in the Eastern African countries. Efficacy at 6-months (93.9%) was estimated on data derived from patients who completed follow up and needs to be interrogated by future studies.

Leonard George Goodwin. 11 July 1915—25 November 2008

For 24 years Leonard George Goodwin was responsible for developing chemotherapeutic agents against parasites at what became the Wellcome Laboratories of Tropical Medicine. Having degrees in pharmacy, physiology and, eventually, clinical medicine, he was active from the start of World War II in the drive to protect Allied forces in the field from tropical diseases. It was in the 1940s, 1950s and into the 1960s that Goodwin had most immediate and lasting impact, through the establishment of five major drugs: sodium stibogluconate, for treatment of leishmaniasis; pyrimethamine, for malaria; piperazine, to combat ascariasis; bephenium, for ankylostomiasis; and phenanthridine derivates, to treat trypanosomiasis. Such agents also became important in veterinary medicine. In 1963 he became director of the new Nuffield Institute of Comparative Medicine and then director of science at the Zoological Society of London. Although Goodwin never worked in higher education, he nonetheless influenced many careers through his involvement with scientific societies.

Therapeutic Response to Thermotherapy in Cutaneous Leishmaniasis Treatment Failures for Sodium Stibogluconate: A Randomized Controlled Proof of Principle Clinical Trial

Treatment failure to intralesional sodium stibogluconate (IL-SSG) is a health challenge for cutaneous leishmaniasis (CL) in Sri Lanka. A randomized controlled proof of principle clinical trial, with two arms (viz., radio frequency–induced heat therapy [RFHT] by a ThermoMed™ device and thermotherapy by a handheld exothermic crystallization thermotherapy for CL [HECT-CL] device) was conducted on 40 CL treatment failures to IL-SSG, from three hospitals in Tangalle, Hambantota, and Anuradhapura, from January 2017 to January 2018, followed up for 180 days post-thermotherapy with a final follow-up in February 2020. Intention-to-treat cure rates were calculated at day 90 (initial cure rate) and at day 180 (final cure rate) posttreatment. Radio frequency–induced heat therapy group: the initial cure rate was 100% (20/20) and the final cure rate was 95% (19/20), with one patient relapsing. The HECT-CL group: both the initial and final cure rates were 80% (16/20), with no relapses and one excluded from the trial. In February 2020 (1.6–3 years posttreatment), 27 traceable patients (RFHT = 16, HECT-CL = 11) remained healed. Second-degree burns were observed with RFHT in 65% (13/20), with HECT-CL in 15% (3/20), which completely resolved subsequently. The cure rates between the two treatment groups were comparable (P = 0.15). Radio frequency–induced heat therapy consumed less time and required only a single hospital visit. Handheld exothermic crystallization thermotherapy for CL is potentially usable at community settings with both being less costly than IL-SSG. This study is the first proof that thermotherapy is an efficacious and safe treatment for CL patients in Sri Lanka, complicated by treatment failure to IL-SSG.