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Programmed‐death‐1 (PD1) antibodies are approved for recurrent and metastatic head and neck squamous cell carcinoma. Multiple drugs targeting costimulatory and coinhibitory immune checkpoint molecules (ICM) have been discovered. However, it remains unknown how these ICM are affected by curative conventional therapy on different immune cell subsets during the course of treatment. In the prospective noninterventional clinical study titled "Immune Response Evaluation to Curative conventional Therapy" (NCT03053661), 22 patients were prospectively enrolled. Blood samples were drawn at defined time points throughout curative conventional treatment and follow‐up. Immune cells (IC) from the different time points were assessed by multicolor flow cytometry. The following ICM were measured by flow cytometry: PD1, CTLA4, BTLA, CD137, CD27, GITR, OX40, LAG3 and TIM3. Dynamics of ICM expression were assessed using nonparametric paired samples tests. Significant changes were noted for PD1, BTLA and CD27 on multiple IC types during or after radiotherapy. Nonsignificant trends for increased expression of OX40 and GITR from baseline until the end of RT were observed on CD4 T cells and CD4+ CD39+ T cells. In patients with samples at recurrence of disease, a nonsignificant increase of TIM3 and LAG3 positive CD4+ CD39+ T cells was evident, accompanied by an increase of double positive cells for TIM3/LAG3. Potential future targets to be combined with RT in the conventional treatment and anti‐PD1/PD‐L could be BTLA agonists, or agonistic antibodies to costimulatory ICM like CD137, OX40 or GITR. The combination of cetuximab with CD27 agonistic antibodies enhancing ADCC or the targeting of TIM3/LAG3 may be another promising strategy. What's new? While standard therapy for HNSCC generally includes surgery plus radiotherapy, immunotherapy for HNSCC is increasing in importance. Here, the authors provide the first prospective clinical study systematically analyzing the expression of 9 different immune checkpoint molecules over multiple time points during conventional therapy and follow up. Radiotherapy, but not surgery, profoundly impacts the expression of immune modulating molecules. Expression of PD1, BTLA, and CD27 changed significantly after radiotherapy, findings which could help improve treatment decisions. BTLA+ cells, for example, declined gradually following radiotherapy, suggesting that targeting BTLA agonists could be a promising strategy. [ABSTRACT FROM AUTHOR]

Nintedanib is a triple angiokinase inhibitor of vascular endothelial growth factor receptor 1‐3, fibroblast growth factor receptor 1‐3 and platelet‐derived growth factor receptor‐a/‐b. Thereby, it targets angiogenic escape mechanisms. The trial TyRosine kinase Inhibitor for the treatment of Chemorefractory Colorectal Cancer (TRICC‐C) trial evaluates the addition of nintedanib to mFOLFOX6 (fluorouracil, folinic acid and oxaliplatin) in patients with metastatic colorectal cancer (mCRC). TRICC‐C is a randomised controlled, double‐blinded, phase II trial in mCRC patients that received a first‐line non‐oxaliplatin containing chemotherapy. Patients received mFOLFOX6 + nintedanib (F + N) (2 × 200 mg p.o./d, d1‐d14) or mFOLFOX6 + placebo (F + P), in a 1:1 ratio. Primary endpoint was median progression free survival (mPFS) and secondary overall response rate (ORR), overall survival (OS) and safety. Fifty‐three patients (27 F + N; 26 F + P) were randomised between 12/2012 and 5/2016 (scheduled n = 180). The trial was terminated prematurely due to slow accrual. The trial did not reach its primary endpoint but mPFS, median overall survival (mOS) and disease control rate (DCR) were numerically higher in the F + N arm compared to the F + P arm; however, the difference was not significant (mPFS: F + P: 4.6 months vs F + N: 8.1 months; HR 0.65; 95% CI 0.32‐1.30; P =.2156; mOS: F + P: 9.9 months vs F + N: 17.1 months; HR 1.03, 95% CI 0.48‐2.23; P =.9387; DCR: F + P: 50% vs F + N: 66,7%; P =.2709). Toxicity was moderate and only different for neutropenia (F + P: 11.5%, F + N: 19.2%) and gastrointestinal disorders (F + P: 65.4%, F + N: 84.6%). Final results show safety and a nonsignificant trend towards improved PFS and DCR for the combination of mFOLFOX6 + nintedanib in the second‐line therapy of mCRC. What's new?: Anti‐angiogenic agents frequently are used in combination with fluorouracil‐based doublet chemotherapy for metastatic colorectal cancer (mCRC) following failure of first‐line therapy. Prolonged use of existing angiogenesis inhibitors, however, fuels the development of resistance, necessitating a search for more effective anti‐angiogenic agents. Here, the authors examined the novel angiogenesis inhibitor nintedanib in combination with modified FOLFOX in second‐line treatment of mCRC. Nintedanib plus mFOLFOX was associated with only modest improvements in survival, a result potentially impacted by slow patient accrual in the trial. Adverse events were comparable to other combination therapies for mCRC, indicating general clinical safety for nintedanib plus mFOLFOX. [ABSTRACT FROM AUTHOR]

Programmed-death-1 (PD1) antibodies are approved for recurrent and metastatic head and neck squamous cell carcinoma. Multiple drugs targeting costimulatory and coinhibitory immune checkpoint molecules (ICM) have been discovered. However, it remains unknown how these ICM are affected by curative conventional therapy on different immune cell subsets during the course of treatment. In the prospective noninterventional clinical study titled "Immune Response Evaluation to Curative conventional Therapy" (NCT03053661), 22 patients were prospectively enrolled. Blood samples were drawn at defined time points throughout curative conventional treatment and follow-up. Immune cells (IC) from the different time points were assessed by multicolor flow cytometry. The following ICM were measured by flow cytometry: PD1, CTLA4, BTLA, CD137, CD27, GITR, OX40, LAG3 and TIM3. Dynamics of ICM expression were assessed using nonparametric paired samples tests. Significant changes were noted for PD1, BTLA and CD27 on multiple IC types during or after radiotherapy. Nonsignificant trends for increased expression of OX40 and GITR from baseline until the end of RT were observed on CD4 T cells and CD4 + CD39 + T cells. In patients with samples at recurrence of disease, a nonsignificant increase of TIM3 and LAG3 positive CD4 + CD39 + T cells was evident, accompanied by an increase of double positive cells for TIM3/LAG3. Potential future targets to be combined with RT in the conventional treatment and anti-PD1/PD-L could be BTLA agonists, or agonistic antibodies to costimulatory ICM like CD137, OX40 or GITR. The combination of cetuximab with CD27 agonistic antibodies enhancing ADCC or the targeting of TIM3/LAG3 may be another promising strategy., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)