The STING agonist IMSA101 enhances chimeric antigen receptor T cell function by inducing IL-18 secretion.

As a strategy to improve the therapeutic success of chimeric antigen receptor T cells (CART) directed against solid tumors, we here test the combinatorial use of CART and IMSA101, a newly developed stimulator of interferon genes (STING) agonist. In two syngeneic tumor models, improved overall survival is observed when mice are treated with intratumorally administered IMSA101 in addition to intravenous CART infusion. Transcriptomic analyses of CART isolated from tumors show elevated T cell activation, as well as upregulated cytokine pathway signatures, in particular IL-18, in the combination treatment group. Also, higher levels of IL-18 in serum and tumor are detected with IMSA101 treatment. Consistent with this, the use of IL-18 receptor negative CART impair anti-tumor responses in mice receiving combination treatment. In summary, we find that IMSA101 enhances CART function which is facilitated through STING agonist-induced IL-18 secretion.

Potentiating adoptive cell therapy using synthetic IL-9 receptors.

Synthetic receptor signalling has the potential to endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumours, including the need for conditioning chemotherapy1,2. Here we designed chimeric receptors that have an orthogonal IL-2 receptor extracellular domain (ECD) fused with the intracellular domain (ICD) of receptors for common γ-chain (γc) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding γc cytokine signal. Of these, T cells that signal through the chimeric orthogonal IL-2Rß-ECD-IL-9R-ICD (o9R) are distinguished by the concomitant activation of STAT1, STAT3 and STAT5 and assume characteristics of stem cell memory and effector T cells. Compared to o2R T cells, o9R T cells have superior anti-tumour efficacy in two recalcitrant syngeneic mouse solid tumour models of melanoma and pancreatic cancer and are effective even in the absence of conditioning lymphodepletion. Therefore, by repurposing IL-9R signalling using a chimeric orthogonal cytokine receptor, T cells gain new functions, and this results in improved anti-tumour activity for hard-to-treat solid tumours.

Inyección epidural de betametasona en el síndrome radicular lumbosacro: evaluación de su eficacia por abordajes interlaminar y transforaminal / Epidural betamethasone injection in lumbosacral radicular syndrome: effi cacy evaluation for interlaminar and transforaminal approaches

Introducción: La betametasona es un esteroide utilizado en las inyecciones epidurales, de reciente incorporación en Uruguay. Objetivos: Evaluar la eficacia de la inyección epidural de betametasona administrada por los abordajes interlaminar parasagital y transforaminal en pacientes con dolor radicular lumbosacro unilateral crónico, utilizando el Inventario Abreviado de Dolor. Material y método: Estudio prospectivo aleatorizado que compara la administración de betametasona por ambos accesos, interlaminar parasagital y transforaminal. El IAD se aplicó previamente y al mes de las inyecciones epidurales. La intensidad del dolor se midió por la Escala Visual Numérica (EVN) obtenida de la pregunta 6 del IAD y el Índice de Intensidad. También se midió la interferencia funcional producida por el dolor mediante el Índice de Interferencia. Se estableció como respuesta satisfactoria un descenso de 2 puntos en la EVN basal al mes de los procedimientos, definiendo a estos pacientes como respondedores. Se utilizó la prueba t de Student y de Chi cuadrado para el análisis estadístico, tomando un valor de p < 0,05 como significancia estadística. Resultados: Un total de 154 pacientes recibieron betametasona epidural. En 29 de ellos se realizó un abordaje interlaminar parasagital y en 25 transforaminal. La betametasona administrada por la vía interlaminar parasagital redujo la puntuación en la EVN un 20 %, y por la vía transforaminal en un 36 %. Estas diferencias fueron estadísticamente signifi cativas cuando se compararon los datos basales y los obtenidos al mes de los procedimientos (prueba t de Student para muestras pareadas), sin encontrarse diferencias estadísticamente significativas entre grupos (prueba t de Student para muestras independientes). Los Índices de Intensidad e Interferencia también fueron reducidos por la inyección epidural de esteroides, sin diferencias significativas entre ambos accesos. La frecuencia de respuestas satisfactorias fue mayor en el grupo tratado por vía transforaminal, 16/25 (64 %) frente a 11/29 (38 %) en el grupo tratado por vía interlaminar, diferencia estadísticamente significativa, con un valor de p = 0,01 (prueba de Chi cuadrado). En aquellos pacientes definidos como respondedores, la betametasona administrada por los dos abordajes produjo una reducción clínica y estadísticamente significativa del dolor y de su repercusión evaluados por el IAD, sin encontrarse diferencias significativas entre los abordajes. Conclusión: La inyección de betametasona epidural administrada por vía interlaminar parasagital y transforaminal redujo la intensidad del dolor y su interferencia funcional en pacientes con dolor radicular crónico. Los abordajes interlaminar parasagital y transforaminal fueron similares en eficacia, aunque con una frecuencia de respuestas satisfactorias mayor en los pacientes tratados por vía transforaminal. La inyección interlaminar parasagital de esteroides es una alternativa válida a la vía transforaminal, sin sus riesgos neurológicos

Introduction: Betamethasone is a frequently used steroid for epidural injection, recently incorporated in the Uruguayan pharmaceutical market. Aims: The aim of this study is to evaluate the efficacy of parasagittal interlaminar and transforaminal epidural betamethasone in unilateral lumbosacral radicular syndrome, utilizing the Brief Pain Inventory (BPI). Material and method: Is a prospective study comparing parasagittal interlaminar and transforaminal epidural betamethasone. Patients with chronic unilateral lumbosacral radicular pain were included. The BPI was administered before and one month after epidural injections. Pain intensity was measured by the Visual Numeric Scale (VNS, question 6 of the BPI) and the Intensity Score. Interference of pain in daily activities was measured by the Interference Score. Satisfactory responses to injections were considered with a 2 points reduction in VNS. The statistical evaluation was performed by paired an unpaired T test to continuous data and Chi Square to evaluate proportions. A p value less than 0.05 was considered statistically significant. Results: Fifty four patients were treated with epidural betamethasone. In 29 the parasagittal interlaminar route was utilized while 25 were treated by the transforaminal route. A 20 % reduction in baseline VNS was observed with the interlaminar route and 36 % reduction with transforaminal approach. Intensity and Interference Scores were also reduced. This reductions were statistically significant when comparing to baseline data (paired t test) but differences between groups were not significant (unpaired t test). However the number of positive responses as defined above was greater in the transforaminal group, 64 % versus 38 % in the interlaminar group, statistically signifi cant difference using the Chi Square analysis (p=0.01). In patients with positive responses, interlaminar and transforaminal betamethasone produce clinical and statistically significant reductions in pain intensity and interference, without difference between groups. Conclusion: Epidural betamethasone produced a reduction in pain intensity and interference utilizing the BPI, by the two routes utilized to access the epidural space. Although no statistically differences were observed in this reductions between groups, the frequency of positive responses were higher when the drug is administered by the transforaminal route. Epidural interlaminar parasagittal betamethasone injection is a reasonable alternative to the transforaminal route, without the neurologic complications described utilizing this technique