Restricting CAR T Cell Trafficking Expands Targetable Antigen Space.

Chimeric antigen receptor (CAR) T cells are an effective treatment for some blood cancers. However, the lack of tumor-specific surface antigens limits their wider use. We identified a set of surface antigens that are limited in their expression to cancer and the central nervous system (CNS). We developed CAR T cells against one of these antigens, LINGO1, which is widely expressed in Ewing sarcoma (ES). To prevent CNS targeting, we engineered LINGO1 CAR T cells lacking integrin α4 (A4ko), an adhesion molecule essential for migration across the blood-brain barrier. A4ko LINGO1 CAR T cells were efficiently excluded from the CNS but retained efficacy against ES. We show that altering adhesion behavior expands the set of surface antigens targetable by CAR T cells.

Targeting the tumor microenvironment of Ewing sarcoma.

Ewing sarcoma is an aggressive tumor type with an age peak in adolescence. Despite the use of dose-intensified chemotherapy as well as radiation and surgery for local control, patients with upfront metastatic disease or relapsed disease have a dismal prognosis, highlighting the need for additional therapeutic options. Different types of immunotherapies have been investigated with only very limited clinical success, which may be due to the presence of immunosuppressive factors in the tumor microenvironment. Here we provide an overview on different factors contributing to Ewing sarcoma immune escape. We demonstrate ways to target these factors in order to make current and future immunotherapies more effective and achieve deeper and more durable responses in patients with Ewing sarcoma.

Lay abstract Ewing sarcoma is an aggressive type of cancer of the bones or soft tissues that mainly affects teenagers. Patients are often treated with intensive treatments which may include chemotherapy in combination with radiation and/or surgery. For patients who present with cancer that has already spread to other sites or that returns after treatment, the cancer can be very hard to cure. This leads to the need for different therapies. Therapies that use the help of the immune system to combat the cancer, called immunotherapies, have had limited success, which is thought to be due to factors in the environment of the tumor that weaken the immune system and so dampen any potential use of it to destroy the cancer cells. We provide an overview of these factors in the tumor environment that allow the cancer cells to escape the immune system; we also discuss potential options to target these factors and, in this way, allow the immunotherapies to destroy the cancer cells more effectively.

Role of immunotherapy in Ewing sarcoma.

Ewing sarcoma (ES) is thought to arise from mesenchymal stem cells and is the second most common bone sarcoma in pediatric patients and young adults. Given the dismal overall outcomes and very intensive therapies used, there is an urgent need to explore and develop alternative treatment modalities including immunotherapies. In this article, we provide an overview of ES biology, features of ES tumor microenvironment (TME) and review various tumor-associated antigens that can be targeted with immune-based approaches including cancer vaccines, monoclonal antibodies, T cell receptor-transduced T cells, and chimeric antigen receptor T cells. We highlight key reasons for the limited efficacy of various immunotherapeutic approaches for the treatment of ES to date. These factors include absence of human leukocyte antigen class I molecules from the tumor tissue, lack of an ideal surface antigen, and immunosuppressive TME due to the presence of myeloid-derived suppressor cells, F2 fibrocytes, and M2-like macrophages. Lastly, we offer insights into strategies for novel therapeutics development in ES. These strategies include the development of gene-modified T cell receptor T cells against cancer-testis antigen such as XAGE-1, surface target discovery through detailed profiling of ES surface proteome, and combinatorial approaches. In summary, we provide state-of-the-art science in ES tumor immunology and immunotherapy, with rationale and recommendations for future therapeutics development.

Saturación sensorial y lactancia materna como métodos analgésicos no farmacológicos: estudio randomizado controlado / Sensory overload and breastfeeding as analgesic method no pharmacologic: control randomized study

OBJETIVO: Verificar el efecto analgésico de la saturación sensorial (Sat) y compararlo con la lactancia materna (LM) y un grupo control. MATERIAL Y MÉTODOS: Ensayo clínico, randomizado con 167 recién nacidos a término sanos, en quiénes se cuantificó la intensidad de dolor agudo al recibir una vacuna (hepatitis B) a las 48 horas de vida. Se formaron tres grupos de manera aleatoria: grupo 1 (control, sin método analgésico), grupo 2 (analgesia con LM) y grupo 3 (analgesia con Sat); los estímulos sensoriales fueron: táctil (caricias de la madre sobre el rostro y espalda), olfatorio (colonia sin alcohol), auditivo (voz de la madre), gustativo (lactancia materna), visual (rostro de la madre frente a su bebé). Se utilizó la Escala para Dolor Agudo Neonatal (DAN: Douleur Aiguë du Nouveau-né), con un score de dolor del 1 al 10 y 7 categorías de dolor. RESULTADOS: El grupo con saturación sensorial tuvo menos dolor (3.02 en la escala de DAN); el grupo dos (lactancia materna): 4.15, y control: 9.02. Hubo diferencia significativa entre grupos. Dolor extremo, se presentó en 60% del grupo control, 3,8% en el grupo lactancia materna y 0% en el grupo con saturación sensorial. La categoría NO DOLOR fue más frecuente en el grupo tres (Sat): 33,3% versus 16,9% del grupo con LM y 0% grupo control, p<0.0001. CONCLUSIONES: La saturación sensorial tuvo mayor efecto analgésico que la lactancia materna. Ambas demostraron buen efecto analgésico, comparadas con el grupo control.

OBJECTIVES: To verify the analgesic effect of sensory overload (SO) and compared with breastfeeding (BF) and a control group. MATERIAL AND METHODS: We conducted a randomized clinical trial in 167 healthy term infants, in which the intensity acute pain was quantified to receive hepatitis B vaccine within 48 hours of life. Three groups were formed at random: one group (control, no method of analgesia), group two (analgesia with BF) and group three (analgesia with SO), sensory stimuli were: touch (petting of the mother on baby face and back), olfactory (colony nonalcoholic), auditory (motherÆs voice), gustatory (breastfeeding), visual (mother and baby - face to face). We used the Neonatal Acute Pain Scale (DAN: Douleur Aigue du Nouveau-né), which gives a pain score of 1 to 10, giving 7 categories of pain. RESULTS: In group three (sensory overload) expressed less pain with an average score of 3.02 on the scale of DAN, the group two (breastfeeding): 4.15, and one group (control): 9.02, with significant difference between groups. The category of extreme pain occurred in 60% of the control group, 3.8% of the breastfed group and there was not extreme pain in the sensory overload group. NO PAIN category was more frequent in all three group (Sat): 33.3% versus 16.9% (group LM) and 0% (control group), p <0.0001. CONCLUSIONS: The sensory overload has greater analgesic effect of breastfeeding. Both demonstrate good analgesic effect compared with the control group.