ICOS and OX40 tandem co-stimulation enhances CAR T-cell cytotoxicity and promotes T-cell persistence phenotype.

Chimeric Antigen Receptor (CAR) T-cell therapies have emerged as an effective and potentially curative immunotherapy for patients with relapsed or refractory malignancies. Treatment with CD19 CAR T-cells has shown unprecedented results in hematological malignancies, including heavily refractory leukemia, lymphoma, and myeloma cases. Despite these encouraging results, CAR T-cell therapy faces limitations, including the lack of long-term responses in nearly 50-70% of the treated patients and low efficacy in solid tumors. Among other reasons, these restrictions are related to the lack of targetable tumor-associated antigens, limitations on the CAR design and interactions with the tumor microenvironment (TME), as well as short-term CAR T-cell persistence. Because of these reasons, we developed and tested a chimeric antigen receptor (CAR) construct with an anti-ROR1 single-chain variable-fragment cassette connected to CD3ζ by second and third-generation intracellular signaling domains including 4-1BB, CD28/4-1BB, ICOS/4-1BB or ICOS/OX40. We observed that after several successive tumor-cell in vitro challenges, ROR1.ICOS.OX40ζ continued to proliferate, produce pro-inflammatory cytokines, and induce cytotoxicity against ROR1+ cell lines in vitro with enhanced potency. Additionally, in vivo ROR1.ICOS.OX40ζ T-cells showed anti-lymphoma activity, a long-lasting central memory phenotype, improved overall survival, and evidence of long-term CAR T-cell persistence. We conclude that anti-ROR1 CAR T-cells that are activated by ICOS.OX40 tandem co-stimulation show in vitro and in vivo enhanced targeted cytotoxicity associated with a phenotype that promotes T-cell persistence.

Clinical characteristics and PD-L1 expression in primary lung squamous cell carcinoma: A case series.

BACKGROUND: Squamous cell lung carcinoma(SCLC), accounts for 20% of lung cancer(LC). The binding of programmed cell death 1(PD-1) to its ligand PD-L1 is a key checkpoint regulator of immune response, and overexpression of the latter leads to immune surveillance escape. This might represent an important oncogenic mechanism, as well as a predictor for immunotherapy treatment success in SCLC. METHODS: A retrospective series of 24 patients with SCLC was included(2009-2013). These patients presented with a single pulmonary lesion and no history of previous cancer. Expression of PD-L1 was evaluated on tumoral biopsies with immunohistochemistry. PD-L1 tumor proportion score(TPS) was considered high when ≥50%. Clinical characteristics regarding diagnosis were reviewed and recorded. Data were analysed in STATA v.14®. RESULTS: Twenty four patients were included in this series. Mean age was 67 + 14 years, and 62.5% were men. Smoking status was positive in 54%. Cancer stage IV was present in 54%. PD-L1 was positive in 13(54%). (+)PD-L1 was more frequent in smokers than in non-smokers(11 vs 2)(p = 0.001), as well as in COPD patients(p = 0.006). General overall survival was 21.8% at 5 years. Overall survival at one year in PD-L1(+) was 30.7% and 72.7% for PD-L1(-) patients. Survival median for PD-L1(+) patients was 10.5mo, as well as for the whole series. CONCLUSION: Patients with primary SCLC who have a high PD-L1 TPS, had a worse overall survival than their counterparts. PD-L1 expression in SCLC in a Colombian sample lies between the one found in the literature.

Post-chikungunya chronic inflammatory rheumatism: results from a retrospective follow-up study of 283 adult and child cases in La Virginia, Risaralda, Colombia.

OBJECTIVE: There are limited studies in Latin America regarding the chronic consequences of the Chikungunya virus (CHIK), such as post-CHIK chronic inflammatory rheumatism (pCHIK-CIR). We assessed the largest cohort so far of pCHIK-CIR in Latin America, at the municipality of La Virginia, Risaralda, a new endemic area of CHIK in Colombia. METHODS: We conducted a cohort retrospective study in Colombia of 283 patients diagnosed with CHIK that persisted with pCHIK-CIR after a minimum of 6 weeks and up to a maximum of 26.1 weeks. pCHIK cases were identified according to validated criteria via telephone. RESULTS: Of the total CHIK-infected subjects, 152 (53.7%) reported persistent rheumatological symptoms (pCHIK-CIR). All of these patients reported joint pains (chronic polyarthralgia, pCHIK-CPA), 49.5% morning stiffness, 40.6% joint edema, and 16.6% joint redness. Of all patients, 19.4% required and attended for care prior to the current study assessment (1.4% consulting rheumatologists). Significant differences in the frequency were observed according to age groups and gender. Patients aged >40 years old required more medical attention (39.5%) than those ≤40 years-old (12.1%) (RR=4.748, 95%CI 2.550-8.840). CONCLUSIONS: According to our results, at least half of the patients with CHIK developed chronic rheumatologic sequelae, and from those with pCHIK-CPA, nearly half presented clinical symptoms consistent with inflammatory forms of the disease. These results support previous estimates obtained from pooled data of studies in La Reunion (France) and India and are consistent with the results published previously from other Colombian cohorts in Venadillo (Tolima) and Since (Sucre).