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Background Immuno-radiotherapy may improve outcomes for patients with advanced solid tumors, although optimized combination modalities remain unclear. Here, we report the colorectal (CRC) cohort analysis from the SABR-PDL1 trial that evaluated the PD-L1 inhibitor atezolizumab in combination with stereotactic body radiation therapy (SBRT) in advanced cancer patients. Methods Eligible patients received atezolizumab 1200 mg every 3 weeks until progression or unmanageable toxicity, together with ablative SBRT delivered concurrently with the 2nd cycle (recommended dose of 45 Gy in 3 fractions, adapted upon normal tissue tolerance constraint). SBRT was delivered to at least one tumor site, with at least one additional measurable lesion being kept from the radiation field. The primary efficacy endpoint was one-year progression-free survival (PFS) rate from the start of atezolizumab. Sequential tumor biopsies were collected for deep multi-feature immune profiling. Results Sixty pretreated (median of 2 prior lines) advanced CRC patients (38 men [63%]; median age, 59 years [range, 20–81 years]; 77% with liver metastases) were enrolled in five centers (France: n  = 4, Spain: n  = 1) from 11/2016 to 04/2019. All but one (98%) received atezolizumab and 54/60 (90%) received SBRT. The most frequently irradiated site was lung ( n  = 30/54; 56.3%). Treatment-related G3 (no G4-5) toxicity was observed in 3 (5%) patients. Median OS and PFS were respectively 8.4 [95%CI:5.9–11.6] and 1.4 months [95%CI:1.2–2.6], including five (9%) patients with PFS > 1 year (median time to progression: 19.2 months, including 2/5 MMR-proficient). Best overall responses consisted of stable disease ( n  = 38; 64%), partial ( n  = 3; 5%) and complete response ( n  = 1; 2%). Immune-centric multiplex IHC and RNAseq showed that SBRT redirected immune cells towards tumor lesions, even in the case of radio-induced lymphopenia. Baseline tumor PD-L1 and IRF1 nuclear expression (both in CD3 + T cells and in CD68 + cells) were higher in responding patients. Upregulation of genes that encode for proteins known to increase T and B cell trafficking to tumors (CCL19, CXCL9), migration (MACF1) and tumor cell killing (GZMB) correlated with responses. Conclusions This study provides new data on the feasibility, efficacy, and immune context of tumors that may help identifying advanced CRC patients most likely to respond to immuno-radiotherapy. Trial registration EudraCT N°: 2015–005464-42; Clinicaltrial.gov number: NCT02992912.

Nanoparticles are of rising interest in cancer research, but in vitro canonical cell monolayer models are not suitable to evaluate their efficacy when prototyping candidates. Here, we developed three-dimensional (3D) spheroid models to test the efficacy of trastuzumab-docetaxel immunoliposomes in breast cancer prior to further testing them in vivo. Immunoliposomes were synthesized using the standard thin film method and maleimide linker. Two human breast cancer cell lines varying in Her2 expression were tested: Her2+ cells derived from metastatic site: mammary breast MDA-MB-453 and triple-negative MDA-MB-231 cells. 3D spheroids were developed and tested with fluorescence detection to evaluate viability. In vivo efficacy and biodistribution studies were performed on xenograft bearing nude mice using fluorescent and bioluminescent imaging. In vitro, antiproliferative efficacy was dependent upon cell type, size of the spheroids, and treatment scheduling, resulting in subsequent changes between tested conditions and in vivo results. Immunoliposomes performed better than free docetaxel + free trastuzumab and ado-trastuzumab emtansine (T-DM1). On MDA-MB-453 and MDA-MB-231 cell growth was reduced by 76% and 25%, when compared to free docetaxel + free trastuzumab and by 85% and 70% when compared to T-DM1, respectively. In vivo studies showed tumor accumulation ranging from 3% up to 15% of the total administered dose in MDA-MB-453 and MDA-MB-231 bearing mice. When compared to free docetaxel + free trastuzumab, tumor growth was reduced by 89% (MDA-MB-453) and 25% (MDA-MB-231) and reduced by 66% (MDA-MB-453) and 29% (MDA-MB-231) when compared to T-DM1, an observation in line with data collected from 3D spheroids experiments. We demonstrated the predictivity of 3D in vitro models when developing and testing nanoparticles in experimental oncology. In vitro and in vivo data showed efficient drug delivery with higher efficacy and prolonged survival with immunoliposomes when compared to current anti-Her2 breast cancer strategies.

The conventional diagnostic and prognostic biomarkers (i.e. Clark Level (CL), Breslow Index (BI) or immunohistochemical markers [2]) seem insufficient to distinguish precisely primary epidermis-limited neoplasms from aggressive or advanced/metastatic melanomas, and to assess the outcome for individual patients. [...]additional relevant biomarkers are needed to predict the individual risk of metastasis and monitor disease progression. [...]we identified several Tspan8 transcriptional regulators whose deregulation leads to Tspan8 expression [3, 5, 6], which could help to design new therapeutic strategies targeting Tspan8. Tspan8 protein expression in human primary melanomas was correlated with a higher propensity to give rise to distant metastases and an increased risk of death To evaluate the impact of Tspan8 expression at the protein level, we performed Tspan8 immunohistochemical staining analysis in a cohort of 100 primary melanoma samples: 73% of primary melanomas were positive for Tspan8 protein expression (sup. Tspan8 protein seemed more frequently expressed in the thinnest melanomas from patients dead during the 5-year period after diagnosis (92.3% of samples). [...]the thinnest primary melanomas seemed to express the highest levels of Tspan8 protein (immunointensity score 4 exclusively in < 1 mm samples), especially in patients’ dead 5-years after diagnosis (60% of immunointensity scores 3–4; Fig. 2c).

Purpose The primary objective of this study was to compare the ability of PET and MRI biomarkers to predict treatment efficacy in a preclinical model of recurrent glioblastoma multiforme. Methods MRI (anatomical, diffusion, vasculature and oxygenation) and PET ([ 18 F]FDG and [ 18 F]FLT) parameters were obtained 3 days after the end of treatment and compared with late tumour growth and survival. Results Early after tumour recurrence, no effect of treatment with temozolomide combined with bevacizumab was observed on tumour volume as assessed by T2-W MRI. At later times, the treatment decreased tumour volume and increased survival. Interestingly, at the earlier time, temozolomide + bevacizumab decreased [ 18 F]FLT uptake, cerebral blood volume and oedema. [ 18 F]FLT uptake, oedema and cerebral blood volume were correlated with overall survival but [ 18 F]FLT uptake had the highest specificity and sensitivity for the early prediction of treatment efficacy. Conclusion The present investigation in a preclinical model of glioblastoma recurrence underscores the importance of multimodal imaging in the assessment of oedema, tumour vascular status and cell proliferation. Finally, [ 18 F]FLT holds the greatest promise for the early assessment of treatment efficacy. These findings may translate clinically in that individualized treatment for recurrent glioma could be prescribed for patients selected after PET/MRI examinations.

Immunoradiotherapy holds promise for improving outcomes in patients with advanced solid tumors, including in soft-tissue sarcoma (STS). However, the ideal combination of treatment modalities remains to be determined, and reliable biomarkers to predict which patients will benefit are lacking. Here, we report the results of the STS cohort of the SABR-PDL1 phase II trial that evaluated the anti-PDL1 atezolizumab combined with stereotactic body radiation therapy (SBRT) delivered concurrently with the 2nd cycle to at least one tumor site. Eligible patients received atezolizumab until progression or unmanageable toxicity, with SBRT at 45 Gy in 3 fractions). The primary endpoint was one-year progression-free survival (PFS) rate with success defined as 13 patients achieving 1-year PFS. Sixty-one heavily pretreated patients with STS (median 5 prior lines; 52% men; median age 54 years; 28% leiomyosarcoma) were enrolled across two centers (France, Spain). SBRT was delivered to 55 patients (90%), with the lung being the most commonly irradiated site (50%). After a median follow-up of 45 months, the one-year PFS rate was 8.3% [95% CI: 3.6–18.1]. Median PFS and overall survival were 2.5 and 8.6 months, respectively. Best responses included partial responses (5%) and stable disease (60%). Immune profiling revealed increased immunosuppressive tumor-associated macrophages (e.g., IL4I1, HES1) and monocyte-recruiting chemokines in non-responders. Higher monocyte/lymphocyte ratios (MonoLR) in tumor and blood correlated with progression. PD-L1 status, lymphoid infiltration, and tertiary-lymphoid structures were not predictive. Although the primary endpoint was not met, this study highlights MonoLR imbalance as a potential biomarker to identify STS patients likely to benefit from immunoradiotherapy. EudraCT No. 2015-005464-42; Clinicaltrial.gov number: NCT02992912.

Trastuzumab plus docetaxel is a mainstay to treat HER2-positive breast cancers. However, developing nanoparticles could help to improve the efficacy/toxicity balance of this doublet by improving drug trafficking and delivery to tumors. This project aimed to develop an immunoliposome in breast cancer, combining docetaxel encapsulated in a stealth liposome engrafted with trastuzumab, and comparing its performances on human breast cancer cell lines with standard combination of docetaxel plus trastuzumab. Several strategies to engraft trastuzumab to pegylated liposomes were tested. Immunoliposomes made of natural (antibody nanoconjugate-1 [ANC-1]) and synthetic lipids (ANC-2) were synthesized using standard thin film method and compared in size, morphology, docetaxel encapsulation, trastuzumab engraftment rates and stability. Antiproliferative activity was tested on human breast cancer models ranging from almost negative (MDA-MB-231), positive (MDA-MB-453) to overexpressing (SKBR3) HER2. Finally, cell uptake of ANC-1 was studied by electronic microscopy. ANC-1 showed a greater docetaxel encapsulation rate (73%±6% vs 53%±4%) and longer stability (up to 1 week) as compared with ANC-2. Both ANC presented particle size ≤150 nm and showed similar or higher in vitro antiproliferative activities than standard treatment, ANC-1 performing better than ANC-2. The IC for docetaxel combined to free trastuzumab were 8.7±4, 2±0.7 and 6±2 nM with MDA-MB-231, MDA-MB-453 and SKBR3, respectively. The IC for ANC-1 were 2.5±1, 1.8±0.6 and 3.4±0.8 nM and for ANC-2 were 1.8±0.3 nM, 2.8±0.8 nM and 6.8±1.8 nM with MDA-MB-231, MDA-MB-453 and SKBR3, respectively. Cellular uptake appeared to depend on HER2 expression, the higher the expression, the higher the uptake. In vitro results suggest that higher antiproliferative efficacy and efficient drug delivery can be achieved in breast cancer models using nanoparticles.

Developing targeted nanoparticles is a rising strategy to improve drug delivery in oncology. Antibodies are the most commonly used targeting agents. However, determination of their optimal number at the surface remains a challenging issue, mainly due to the difficulties in measuring precisely surface coating levels when prototyping nanoparticles. We developed an original quantitative assay to measure the exact number of coated antibodies per nanoparticle. Using flow cytometry optimized for submicron particle analysis and beads covered with known amounts of human IgG-kappa mimicking various amounts of antibodies, this new method was tested as part of the prototyping of docetaxel liposomes coated with trastuzumab against Her2+ breast cancer. This quantification method allowed to discriminate various batches of immunoliposomes depending on their trastuzumab density on nanoparticle surface (i.e., 330 (Immunoliposome-1), 480 (Immunoliposome-2) and 690 (Immunoliposome-3), p = 0.004, One-way ANOVA). Here we showed that optimal number of grafted antibodies on nanoparticles should be finely tuned and highest density of targeting agent is not necessarily associated with highest efficacy. Overall, this new method should help to better prototype third generation nanoparticles.

From 3D spheroids to tumor bearing mice: efficacy and distribution studies of trastuzumab-docetaxel immunoliposome in breast cancer [Erratum]Rodallec A, Sicard G, Giacometti S, et al. Int J Nano. 2018;13: 6677-6688.On page 6684, Table 1 should be as follows:Read the original article

The primary objective of this study was to compare the ability of PET and MRI biomarkers to predict treatment efficacy in a preclinical model of recurrent glioblastoma multiforme.PURPOSEThe primary objective of this study was to compare the ability of PET and MRI biomarkers to predict treatment efficacy in a preclinical model of recurrent glioblastoma multiforme.MRI (anatomical, diffusion, vasculature and oxygenation) and PET ([(18)F]FDG and [(18)F]FLT) parameters were obtained 3 days after the end of treatment and compared with late tumour growth and survival.METHODSMRI (anatomical, diffusion, vasculature and oxygenation) and PET ([(18)F]FDG and [(18)F]FLT) parameters were obtained 3 days after the end of treatment and compared with late tumour growth and survival.Early after tumour recurrence, no effect of treatment with temozolomide combined with bevacizumab was observed on tumour volume as assessed by T2-W MRI. At later times, the treatment decreased tumour volume and increased survival. Interestingly, at the earlier time, temozolomide + bevacizumab decreased [(18)F]FLT uptake, cerebral blood volume and oedema. [(18)F]FLT uptake, oedema and cerebral blood volume were correlated with overall survival but [(18)F]FLT uptake had the highest specificity and sensitivity for the early prediction of treatment efficacy.RESULTSEarly after tumour recurrence, no effect of treatment with temozolomide combined with bevacizumab was observed on tumour volume as assessed by T2-W MRI. At later times, the treatment decreased tumour volume and increased survival. Interestingly, at the earlier time, temozolomide + bevacizumab decreased [(18)F]FLT uptake, cerebral blood volume and oedema. [(18)F]FLT uptake, oedema and cerebral blood volume were correlated with overall survival but [(18)F]FLT uptake had the highest specificity and sensitivity for the early prediction of treatment efficacy.The present investigation in a preclinical model of glioblastoma recurrence underscores the importance of multimodal imaging in the assessment of oedema, tumour vascular status and cell proliferation. Finally, [(18)F]FLT holds the greatest promise for the early assessment of treatment efficacy. These findings may translate clinically in that individualized treatment for recurrent glioma could be prescribed for patients selected after PET/MRI examinations.CONCLUSIONThe present investigation in a preclinical model of glioblastoma recurrence underscores the importance of multimodal imaging in the assessment of oedema, tumour vascular status and cell proliferation. Finally, [(18)F]FLT holds the greatest promise for the early assessment of treatment efficacy. These findings may translate clinically in that individualized treatment for recurrent glioma could be prescribed for patients selected after PET/MRI examinations.

Melanoma, the most serious form of skin cancer, frequently involves the dysregulation of key signaling pathways. Treatment strategies presently target the MAPK/ERK pathway, which is overactive in melanomas due in part to BRAF and NRAS mutations, and involve inhibitors against mutated BRAF (vemurafenib or dabrafenib) or MEK kinases (cobimetinib or trametinib), or a combination of the two. Using an established biochip technology, we assessed base excision repair (BER) and nucleotide excision repair (NER) activities in a collection of BRAF mutated (A-375, Colo 829, HT-144, Malme-3M, SK-mel5, SK-mel24 and SK-mel28) and NRAS mutated (M18, MZ2 and SK-mel2) melanoma cell lines, as well as wild-type controls (A7, CHL-1). We evaluated both basal activities (i.e., without treatment) and repair capacities after treatment with vemurafenib or cobimetinib alone, or in combination. Our results indicate that globally the DNA repair capacity of the cell lines was determined by the mutation status of the BRAF and NRAS genes, indicating that the MAPK pathway participates in the regulation of both BER and NER. Treatment of BRAF mutated melanoma cells with vemurafenib alone or the vemurafenib/cobimetinib combination, but not cobimetinib alone, led to reduced DNA repair capacity in about 60% of the BRAF mutated samples, indicating that signaling pathway inhibition can alter DNA repair activity. Upregulation of some DNA repair activities was also observed in several of the treated samples, suggesting activation of compensatory signaling pathways upon treatment. The data collectively indicate that mutations in the BRAF and NRAS genes exert distinct regulatory effects on the excision/synthesis steps of the BER and NER pathways and that targeted pharmacological inactivation of the signaling mechanism can translate into specific consequences in DNA repair capacity. The heterogeneity of the responses reported herein could help define subtypes of melanoma that are associated with resistance to targeted therapies.