Background Anti-PD-(L)1 agents are standard of care treatments in various cancers but predictive factors for therapy selection are limited. We hypothesised that markers of systemic inflammation would predict adverse outcomes in multiple cancers treated with anti-PD-(L)1 agents. Material and methods Discovery cohort consisted of patients who were treated with anti-programmed cell death protein-1 (PD-1) agents for advanced melanoma (MEL), non-small cell lung cancer (NSCLC) or renal and bladder cancers (GU) at Oulu University Hospital and had pretreatment C reactive protein (CRP), or neutrophil/lymphocyte values available. As a validation cohort, we collected patients treated with anti-PD-1 agents from three other hospitals in Finland. Results In the discovery cohort (n=56, MEL n=23, GU n=17, NSCLC n=16), elevated CRP over the upper limit of normal (ULN) (>10mg/mL) indicated poor progression-free (PFS; p=0.005) and overall survival (OS; p=0.000004) in the whole population and in MEL subgroup. Elevated neutrophil-to-lymphocyte ratio (>2.65) also indicated inferior PFS (p=0.02) and OS (p=0.009). In the validation cohort (n=107,MEL n=44, NSCLC n=42, GU n=17, other n=4), CRP over ULN also was a strong indicator for poor PFS (p=0.0000008), and OS (p=0.000006) in the whole population, and in MEL and NSCLC also. Conclusions Systemic inflammation suggested by elevated CRP is a very strong indicator for adverse prognosis on patients treated with anti-PD-(L)1 agents and has a potential negative predictive value for treatment with anti-PD-(L)1 agents. Prospective trials should investigate whether patients with elevated CRP gain any significant benefit from anti-PD-1 therapy.

Objective: Immune checkpoint inhibitors (ICI) can cause endocrine adverse events. However, endocrine AEs could be related to better treatment outcomes. Our aim was to investigate whether this holds true in a real-world setting of metastatic melanoma patients. Design: A retrospective single-institution study. Methods: We included 140 consecutive metastatic melanoma patients treated with ICI between January 2012 and May 2019. We assessed the endocrine toxicity and the best possible treatment outcomes from electronic patient records, including laboratory parameters and radiological images. Results: Of the treated patients, 21 patients (15%) were treated with ipilimumab, 46 (33%) with nivolumab, 67 (48%) with pembrolizumab, and 6 (4%) with combination therapy (ipilimumab + nivolumab). Endocrine AEs appeared in 29% (41/140) patients. Three patients had two different endocrine AEs. Thyroid disorders were the most common: 26% (36/140), followed by hypophysitis: 4% (5/140). Three subjects (2%, 3/140) were diagnosed with autoimmune diabetes. Three patients had to terminate treatment due to endocrine toxicity. Radiological manifestations of endocrine AEs were found in 16 patients (39%, 16/41). Endocrine toxicity was associated with significantly better treatment outcomes. Median progression-free survival (8.1 months, range 5.1-11.1 months vs 2.7 months, range 2.4-3.0 months, P < 0.001), and median overall survival (47.5 months, range 15.5-79.5 months vs 23.7 months, range 15.3-32.1 months, P = 0.035) were longer for patients experiencing endocrine AEs. Conclusions: The higher number of endocrine AEs suggest that regular laboratory monitoring aids in AE detection. Endocrine AEs in metastatic melanoma may correlate with better treatment outcomes.

Oncolytic virotherapy is an emerging therapeutic approach based on replication-competent viruses able to selectively infect and destroy cancer cells, inducing the release of tumor-associated antigens and thereby recruiting immune cells with a subsequent increase in antitumoral immune response. To increase the anticancer activity, we engineered a specific oncolytic adenovirus expressing a single-chain variable fragment of an antibody against PD-L1 to combine blockage of PD-1/PD-L1 interaction with the antitumoral activity of Onc.Ad5. To assess its efficacy, we infected B16.OVA cells, a murine model of melanoma, with Ad5 Delta 24 -anti-PD-L1-scFv and then co-cultured them with C57BL/6J naive splenocytes. We observed that the combinatorial treatments were significantly more effective in inducing cancer cell death. Furthermore, we assessed the efficacy of intratumoral administrations of Ad5 Delta 24-anti-PD-L1-scFv in C57BL/6J mice engrafted with B16.OVA and compared this treatment to that of the parental Ad5 Delta 24 or placebo. Treatment with the scFv-expressing Onc.Ad induced a marked reduction of tumor growth concerning the parental Onc.Ad. Additionally, the evaluation of the lymphocytic population infiltrating the treated tumor reveals a favorable immune profile with an enhancement of the CD8(+) population. These data suggest that Onc.Ad-mediated expression of immune checkpoint inhibitors increases oncolytic virotherapy efficacy and could be an effective and promising tool for cancer treatments, opening a new way into cancer therapy.

Background Oncolytic viruses are a potent form of active immunotherapy, capable of invoking antitumor T-cell responses. Meanwhile, less is known about their effects on immune checkpoints, the main targets for passive immunotherapy of cancer. T-cell immunoglobulin and mucin domain-3 (TIM-3) is a coinhibitory checkpoint driving T-cell exhaustion in cancer. Here we investigated the effects of oncolytic adenovirus on the TIM-3 checkpoint on tumor-infiltrating immune cells and clinical impact in patients with cancer receiving oncolytic immunotherapy. Methods Modulation of TIM-3 expression on tumor-infiltrating immune cells was studied preclinically in B16 melanoma following intratumoral treatment with Ad5/3 increment 24-granulocyte-macrophage colony-stimulating factor oncolytic adenovirus. We conducted a retrospective longitudinal analysis of 15 patients with advanced-stage cancer with tumor-site biopsies before and after oncolytic immunotherapy, treated in the Advanced Therapy Access Program (ISRCTN10141600, April 5, 2011). Following patient stratification with regard to TIM-3 (increase vs decrease in tumors), overall survival and imaging/marker responses were evaluated by log-rank and Fisher's test, while coinhibitory receptors/ligands, transcriptomic changes and tumor-reactive and tumor-infltrating immune cells in biopsies and blood samples were studied by microarray rank-based statistics and immunoassays. Results Preclinically, TIM-3(+) tumor-infiltrating lymphocytes (TILs) in B16 melanoma showed an exhausted phenotype, whereas oncolytic adenovirus treatment significantly reduced the proportion of TIM-3(+) TIL subset through recruitment of less-exhausted CD8(+) TIL. Decrease of TIM-3 was observed in 60% of patients, which was associated with improved overall survival over TIM-3 increase patients (p=0.004), together with evidence of clinical benefit by imaging and blood analyses. Coinhibitory T-cell receptors and ligands were consistently associated with TIM-3 changes in gene expression data, while core transcriptional exhaustion programs and T-cell dysfunction were enriched in patients with TIM-3 increase, thus identifying patients potentially benefiting from checkpoint blockade. In striking contrast, patients with TIM-3 decrease displayed an acute inflammatory signature, redistribution of tumor-reactive CD8(+) lymphocytes and higher influx of CD8(+) TIL into tumors, which were associated with the longest overall survival, suggesting benefit from active immunotherapy. Conclusions Our results indicate a key role for the TIM-3 immune checkpoint in oncolytic adenoviral immunotherapy. Moreover, our results identify TIM-3 as a potential biomarker for oncolytic adenoviruses and create rationale for combination with passive immunotherapy for a subset of patients.

Ohutsuolisyöpä on harvinainen ruoansulatuskanavan syöpä, jonka ennuste on huono, sillä se yleensä havaitaan vasta pitkälle edenneenä lievien ja epäspesifien oireiden vuoksi. Adenokarsinooma on toiseksi yleisin syövän histologinen alatyyppi, joka esiintyy ohutsuolessa. Useissa eri syövissä elimistön immuunipuolustusreaktion voimakkuutta on käytetty syöpien ennustetta arvioidessa. T-lymfosyyttien (CD3+, CD8+) määrästä ja sijainnista muodostettavaa Immune Cell Score (ICS)-pisteytysjärjestelmää voidaan käyttää syövissä, kuten paksusuolisyövässä, perinteisen TNM-luokituksen ohella, ennusteellisena työkaluna. Sen sijaan immuunivastetta hiljentävästä PD-1/PD-L1- reitin aktivaatiosta syövän ennusteellisena tekijänä on ristiriitaista näyttöä. Ohutsuolen adenokarsinoomassa immunologisten parametrien ennusteellista arvoa ei ole juuri aiemmin arvioitu. Tavoitteenamme oli arvioida syövän ympäristössä esiintyvien tulehdussolujen piirteiden korrelaatiota taudin ennusteeseen. Analysoimme syöpäkasvaimien sytotoksisten T-lymfosyyttien (CD3+, CD8+) tiheydet syöpäsolukossa sekä terveen kudoksen ja syöpäkudoksen rajalla. Näiden perusteella luokittelimme syöpäkasvaimet Immune Cell Score-luokkiin Vertasimme Immune Cell Scoren vaikutusta taudin ennusteeseen. Lisäksi analysoimme PD-1 ja PD-L1 ilmentymistä syöpään tunkeutuvien tulehdussolujen ja syöpäsolujen pinnalla. PD-1/PD-L1 ilmentymisen vaikutusta vertasimme taudin tautispesifiin- ja kokonaiselossaoloon. Muodostimme edelleen näistä kolmesta immunologisesta parametrista (ICS, PD-1 ja PD-L1) syövälle Immunoprofiilin ja arvioimme Immunoprofiili-luokan vaikutusta taudin ennusteeseen. Yksittäisinä muuttujina PD-1:n voimakas ilmentyminen, PD-L1:n runsas ilmentyminen syövän sisään tunkeutuvissa tulehdussoluissa ja korkea Immune Cell Score vaikuttivat myönteisesti tautikohtaiseen- ja kokonaisennusteeseen. Pelkästään voimakas PD-L1:n ilmentyminen syöpäsolukkoon tunkeutuvien tulehdussolujen pinnalla osoitti itsenäistä ennusteellista arvoa monimuuttuja-analyysissä. Lisäksi korkea Immunoprofiili-luokka antoi merkityksellistä informaatiota taudin ennusteesta.

T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on lymphocytes that was recently propelled under the spotlight as a major emerging target in cancer immunotherapy. TIGIT interacts with CD155 expressed on antigen-presenting cells or tumour cells to down-regulate T cell and natural killer (NK) cell functions. TIGIT has emerged as a key inhibitor of anti-tumour responses that can hinder multiple steps of the cancer immunity cycle. Pre-clinical studies indicated that TIGIT blockade may protect against various solid and haematological cancers. Several monoclonal antibodies (mAbs) that block the inhibitory activity of human TIGIT have been developed. Clinical trials are ongoing, investigating TIGIT blockade as a monotherapy or in combination with anti-PD1/PD-L1 mAbs for the treatment of patients with advanced solid malignancies. In this review, we cover our current knowledge on TIGIT, from its discovery in 2009 to its current status as a clinical target.