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Background: Patients with hematological malignancies are at greater risk of severe COVID-19 and have been prioritized for COVID-19 vaccination. A significant proportion of them have an impaired vaccine response, both due to the underlying disease and to the treatments. Methods: We conducted a prospective observational study to identify the specific risks of the outpatient population with hematological diseases. Result: Between 22 December 2021 to 12 February 2022, we followed 338 patients of which 16.9% (n = 57) developed SARS-CoV-2 infection despite previous vaccination (94.7%). COVID-19 patients were more likely to have received immunotherapy (85.5% vs. 41%, p < 10−4), and particularly anti-CD20 monoclonal antibodies (40% vs. 14.9%, p < 10−4) and Bruton’s tyrosine kinase inhibitors (BTKi) (7.3% vs. 0.7%, p < 10−2). There was no significant difference in demographic characteristics or hematological malignancies between COVID-19-positive and non-positive patients. Patients hospitalized for COVID-19 had more frequently received immunotherapy than patients with asymptomatic or benign forms (100% vs. 77.3%, p < 0.05). Hospitalized COVID-19 patients had a higher proportion of negative or weakly positive serologies than non-hospitalized patients (92.3% vs. 61%, p < 0.05). Patients who received tixagevimab/cilgavimab prophylaxis (n = 102) were less likely to be COVID-19-positive (4.9 vs. 22%, p < 0.05) without significant difference in hospitalization rates. Conclusion: In the immunocompromised population of patients with hematological malignancies, the underlying treatment of blood cancer by immunotherapy appears to be a risk factor for SARS-CoV-2 infection and for developing a severe form.

Immunotherapy based on two checkpoint inhibitors (ICI), programmed cell death 1 (PD-1, Nivolumab) and cytotoxic T-lymphocyte 4 (CTLA-4, Ipilimumab), has provided a significant improvement in overall survival for malignant mesothelioma (MM). Despite this major breakthrough, the median overall survival of patients treated with the two ICIs only reached 18.1 months vs. 14 months in standard chemotherapy. With an objective response rate of 40%, only a subset of patients benefits from immunotherapy. A critical step in the success of immunotherapy is the presentation of tumor-derived peptides by the major histocompatibility complex I (MHC-I) of tumor cells. These neoantigens are potentially immunogenic and trigger immune responses orchestrated by cytotoxic cells. In MM, tumor development is nevertheless characterized by a low mutation rate despite major structural chromosomal rearrangements driving oncogenesis (BAP1, NF2, CDKN2AB). In this opinion, we propose to investigate an approach based on the mechanisms of the DNA damage tolerance (DDT) pathways to increase the frequency of non-synonymous mutations. The idea is to transiently activate the error-prone DDT in order to generate neoantigens while preserving a fully competent antitumor immune response.

Despite the lack of approved anti-angiogenic therapies in squamous cell carcinoma of the head and neck (SCCHN), preclinical and more recent clinical evidence support the role of targeting the vascular endothelial growth factor (VEGF) in this disease. Targeting VEGF has gained even greater interest following the recent evidence supporting the role of immunotherapy in the management of advanced SCCHN. Preclinical evidence strongly suggests that VEGF plays a role in promoting the growth and progression of SCCHN, and clinical evidence exists as to the value of combining this strategy with immunotherapeutic agents. Close to 90% of SCCHNs express VEGF, which has been correlated with a worse clinical prognosis and an increased resistance to chemotherapeutic agents. As immunotherapy is currently at the forefront of the management of advanced SCCHN, revisiting the rationale for targeting angiogenesis in this disease has become an even more attractive proposition.

Although anti-CD38 monoclonal antibodies have improved the prognosis of relapsed/refractory multiple myeloma (RRMM), some patients still experience early relapses with poor outcomes. This present study evaluated the predictive value of FDG PET/CT parameters for RRMM prior to initiating anti-CD38 treatment. We included 38 consecutive RRMM patients who underwent a PET/CT scan treated at our institution at relapse. The median PFS was 12.5 months and the median OS was not reached. 42% of the patients had an initial ISS score of 1, 37% of 2, and 21% of 3. The presence of >3 focal lesions (FLs, n = 19) and the ISS score were associated with inferior PFS (p = 0.0036 and p = 0.0026) and OS (p = 0.025 and p = 0.0098). Patients with >3 FLs had a higher initial ISS score (p = 0.028). In multivariable analysis, the ISS score and >3 FLs were independent prognostic factors for PFS (p = 0.010 and p = 0.025 respectively), and combined they individualized a high-risk group with a median PFS and OS of 3.1 months and 8.5 months respectively vs. not reached for the other patients. The presence of >3 FLs on PET was predictive of survival outcomes in patients with RRMM treated using CD38 targeted therapy. Combined with the initial ISS, an ultra-high-risk RRMM population can thus be identified.

Simple Summary: Immunotherapy is increasingly used in lymphoma strategy. Risk-adapted therapeutical management and set-up scores to -stratify the most vulnerable patients by risk are becoming major concerns. With the continuing upward trend of real-world data usage in addition to clinical trial data, it is possible to test the feasibility of using data from clinical data warehouses (CDWs) to identify new predictive factors for response or toxicity to immunotherapy. Based on a large set of biological and clinical factors, our results confirm already known predictors factors of CAR T (chimeric antigen receptor T) cells: age, elevated lactate dehydrogenase, and C-Reactive Protein at the time of infusion. Additionally male gender, low hemoglobin, and hypo- or hyperkalemia are demonstrated to be predictive factors for progression after CAR T cell therapy. Thus, the attractiveness of CDW for generating data by building ever larger cohorts is proven, enabling significant results to be obtained in line with those previously described in the literature. Immunotherapy (IT) is a major therapeutic strategy for lymphoma, significantly improving patient prognosis. IT remains ineffective for a significant number of patients, however, and exposes them to specific toxicities. The identification predictive factors around efficacy and toxicity would allow better targeting of patients with a higher ratio of benefit to risk. PRONOSTIM is a multicenter and retrospective study using the Clinical Data Warehouse (CDW) of the Greater Paris University Hospitals network. Adult patients with Hodgkin lymphoma or diffuse large-cell B lymphoma treated with immune checkpoint inhibitors or CAR T (Chimeric antigen receptor T) cells between 2017 and 2022 were included. Analysis of covariates influencing progression-free survival (PFS) or the occurrence of grade ≥3 toxicity was performed. In total, 249 patients were included. From this study, already known predictors for response or toxicity of CAR T cells such as age, elevated lactate dehydrogenase, and elevated C-Reactive Protein at the time of infusion were confirmed. In addition, male gender, low hemoglobin, and hypo- or hyperkalemia were demonstrated to be potential predictive factors for progression after CAR T cell therapy. These findings prove the attractiveness of CDW in generating real-world data, and show its essential contribution to identifying new predictors for decision support before starting IT. [ABSTRACT FROM AUTHOR]

Background: Patients with hematological malignancies are at greater risk of severe COVID-19 and have been prioritized for COVID-19 vaccination. A significant proportion of them have an impaired vaccine response, both due to the underlying disease and to the treatments. Methods: We conducted a prospective observational study to identify the specific risks of the outpatient population with hematological diseases. Result: Between 22 December 2021 to 12 February 2022, we followed 338 patients of which 16.9% (n = 57) developed SARS-CoV-2 infection despite previous vaccination (94.7%). COVID-19 patients were more likely to have received immunotherapy (85.5% vs. 41%, p < 10−4), and particularly anti-CD20 monoclonal antibodies (40% vs. 14.9%, p < 10−4) and Bruton's tyrosine kinase inhibitors (BTKi) (7.3% vs. 0.7%, p < 10−2). There was no significant difference in demographic characteristics or hematological malignancies between COVID-19-positive and non-positive patients. Patients hospitalized for COVID-19 had more frequently received immunotherapy than patients with asymptomatic or benign forms (100% vs. 77.3%, p < 0.05). Hospitalized COVID-19 patients had a higher proportion of negative or weakly positive serologies than non-hospitalized patients (92.3% vs. 61%, p < 0.05). Patients who received tixagevimab/cilgavimab prophylaxis (n = 102) were less likely to be COVID-19-positive (4.9 vs. 22%, p < 0.05) without significant difference in hospitalization rates. Conclusion: In the immunocompromised population of patients with hematological malignancies, the underlying treatment of blood cancer by immunotherapy appears to be a risk factor for SARS-CoV-2 infection and for developing a severe form. [ABSTRACT FROM AUTHOR]

Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO's MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC. Immune checkpoint blockade has become standard care for patients with recurrent metastatic head and neck squamous cell carcinoma (HNSCC). Here the authors present the results of a non-randomized phase Ib/IIa trial, reporting safety and efficacy of neoadjuvant nivolumab monotherapy and nivolumab plus ipilimumab prior to standard-of-care surgery in patients with HNSCC.. [ABSTRACT FROM AUTHOR]

Aims: Programmed death‐ligand 1 (PD‐L1) immunostaining is used to predict which non‐small‐cell lung cancer (NSCLC) patients will respond best to treatment with programmed cell death protein 1/PD‐L1 inhibitors. PD‐L1 immunostaining is sometimes performed on alcohol‐fixed cytological specimens instead of on formalin‐fixed paraffin‐embedded (FFPE) biopsies or resections. We studied whether ethanol prefixation of clots from endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA) results in diminished PD‐L1 immunostaining as compared with formalin fixation. Methods and results: FFPE cell blocks from EBUS‐TBNA specimens of 54 NSCLC patients were identified. For each case, paired samples were available, consisting of clots directly immersed in formalin and clots prefixed in Fixcyt (50% ethanol). Serial sections were immunostained for PD‐L1 by use of the standardised SP263 assay and the 22C3 antibody as a laboratory‐developed test (LDT). PD‐L1 positivity was determined with two cut‐offs (1% and 50%). Concordance of PD‐L1 positivity between the formalin‐fixed (gold standard) and ethanol‐prefixed material was assessed. When the 22C3 LDT was used, 30% and 36% of the ethanol‐prefixed specimens showed false‐negative results at the 1% and 50% cut‐offs, respectively (kappa 0.64 and 0.68). When SP263 was used, 22% of the ethanol‐prefixed specimens showed false‐negative results at the 1% cut‐off (kappa 0.67). At the 50% cut‐off, concordance was higher (kappa 0.91), with 12% of the ethanol‐prefixed specimens showing false‐negative results. Conclusion: Ethanol fixation of EBUS‐TBNA specimens prior to formalin fixation can result in a considerable number of false‐negative PD‐L1 immunostaining results when a 1% cut‐off is used and immunostaining is performed with SP263 or the 22C3 LDT. The same applies to use of the 50% cut‐off when immunostaining is performed with the 22C3 LDT. [ABSTRACT FROM AUTHOR]

Background: As a consequence of the discovery of an extracellular component responsible for the progression of tau pathology, tau immunotherapy is being extensively explored in both preclinical and clinical studies as a disease modifying strategy for the treatment of Alzheimer's disease.Objective: Describe the characteristics of the anti-phospho (T212/T217) tau selective antibody PT3 and its humanized variant hPT3.Methods: By performing different immunization campaigns, a large collection of antibodies has been generated and prioritized. In depth, in vitro characterization using surface plasmon resonance, phospho-epitope mapping, and X-ray crystallography experiments were performed. Further characterization involved immunohistochemical staining on mouse- and human postmortem tissue and neutralization of tau seeding by immunodepletion assays.Results and Conclusion: Various in vitro experiments demonstrated a high intrinsic affinity for PT3 and hPT3 for AD brain-derived paired helical filaments but also to non-aggregated phospho (T212/T217) tau. Further functional analyses in cellular and in vivo models of tau seeding demonstrated almost complete depletion of tau seeds in an AD brain homogenate. Ongoing trials will provide the clinical evaluation of the tau spreading hypothesis in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Programmed cell death ligand 1 (PD‐L1) immunohistochemistry is used to determine which patients with advanced non‐small‐cell lung cancer (NSCLC) respond best to treatment with PD‐L1 inhibitors. For each inhibitor, a unique immunohistochemical assay was developed. This systematic review gives an up‐to‐date insight into the comparability of standardised immunohistochemical assays and laboratory‐developed tests (LDTs), focusing specifically on tumour cell (TC) staining and scoring. A systematic search was performed identifying publications that assessed interassay, interobserver and/or interlaboratory concordance of PD‐L1 assays and LDTs in tissue of NSCLC patients. Of 4294 publications identified through the systematic search, 27 fulfilled the inclusion criteria and were of sufficient methodological quality. Studies assessing interassay concordance found high agreement between assays 22C3, 28‐8 and SP263 and properly validated LDTs, and lower concordance for comparisons involving SP142. A decrease in concordance, however, is seen with use of cut‐offs, which hampers interchangeability of PD‐L1 immunohistochemistry assays and LDTs. Studies assessing interobserver concordance found high agreement for all assays and LDTs, but lower agreement with use of a 1% cut‐off. This may be problematic in clinical practice, as discordance between pathologists at this cut‐off may result in some patients being denied valuable treatment options. Finally, five studies assessed interlaboratory concordance and found moderate to high agreement levels for various assays and LDTs. However, to assess the actual existence of interlaboratory variation in PD‐L1 testing and PD‐L1 positivity in clinical practice, studies using real‐world clinical pathology data are needed. [ABSTRACT FROM AUTHOR]

Simple Summary: A critical step in the success of immunotherapy is the presentation of tumor-derived peptides by the major histocompatibility complex I (MHC-I) of tumor cells. These neoantigens are potentially immunogenic and trigger immune responses orchestrated by cytotoxic cells. In malignant mesothelioma (MM), tumor development is nevertheless characterized by a low mutation rate despite major structural chromosomal rearrangements driving oncogenesis. In this paper, we propose a paradigm based on the mechanisms of the DNA damage tolerance (DDT) pathways to increase the frequency of non-synonymous mutations. The idea is to transiently activate the error-prone DDT in order to generate neoantigens while preserving a fully competent antitumor immune response. Immunotherapy based on two checkpoint inhibitors (ICI), programmed cell death 1 (PD-1, Nivolumab) and cytotoxic T-lymphocyte 4 (CTLA-4, Ipilimumab), has provided a significant improvement in overall survival for malignant mesothelioma (MM). Despite this major breakthrough, the median overall survival of patients treated with the two ICIs only reached 18.1 months vs. 14 months in standard chemotherapy. With an objective response rate of 40%, only a subset of patients benefits from immunotherapy. A critical step in the success of immunotherapy is the presentation of tumor-derived peptides by the major histocompatibility complex I (MHC-I) of tumor cells. These neoantigens are potentially immunogenic and trigger immune responses orchestrated by cytotoxic cells. In MM, tumor development is nevertheless characterized by a low mutation rate despite major structural chromosomal rearrangements driving oncogenesis (BAP1, NF2, CDKN2AB). In this opinion, we propose to investigate an approach based on the mechanisms of the DNA damage tolerance (DDT) pathways to increase the frequency of non-synonymous mutations. The idea is to transiently activate the error-prone DDT in order to generate neoantigens while preserving a fully competent antitumor immune response. [ABSTRACT FROM AUTHOR]

Simple Summary: Therapies for squamous cell carcinomas of the head and neck (SCCHN) have been rapidly evolving, initially with the inclusion of immunotherapy, but more recently with the consideration of anti-angiogenic therapies. Recent preclinical and clinical data reveal a strong correlation between vascular endothelial growth factor (VEGF) and the progression of SCCHN, with nearly 90% of these malignancies expressing VEGF. Our review article not only elaborates on the utility of anti-VEGF therapies on SCCHN but also its interaction with the immune environment. Furthermore, we detailed the current data on immunotherapies targeting SCCHN and how this could be coupled with anti-angiogenics therapies. Despite the lack of approved anti-angiogenic therapies in squamous cell carcinoma of the head and neck (SCCHN), preclinical and more recent clinical evidence support the role of targeting the vascular endothelial growth factor (VEGF) in this disease. Targeting VEGF has gained even greater interest following the recent evidence supporting the role of immunotherapy in the management of advanced SCCHN. Preclinical evidence strongly suggests that VEGF plays a role in promoting the growth and progression of SCCHN, and clinical evidence exists as to the value of combining this strategy with immunotherapeutic agents. Close to 90% of SCCHNs express VEGF, which has been correlated with a worse clinical prognosis and an increased resistance to chemotherapeutic agents. As immunotherapy is currently at the forefront of the management of advanced SCCHN, revisiting the rationale for targeting angiogenesis in this disease has become an even more attractive proposition. [ABSTRACT FROM AUTHOR]

Simple Summary: Anti-CD38 monoclonal antibody has improved the prognosis of relapsed/refractory multiple myeloma (RRMM) but some patients still experience early relapse with a poor outcome. We have here evaluated the predictive value of FDG PET/CT parameters prior to receiving anti-CD38-based therapy in RRMM cases. In 38 consecutive patients, the median PFS was 12.5 months and the median OS was not reached. The presence of >3 focal lesions (FLs) on relapse PET (n = 19) and the initial ISS were associated with both an inferior PFS (p = 0.0036 and p = 0.0026) and OS (p = 0.025 and p = 0.0098). In multivariable analysis, the ISS and >3 FLs were independent prognostic factors for PFS (p = 0.010 and p = 0.025). A prognostic score combining the ISS (1,2, or 3 points) and >3 FL (1 point) individualized an ultra-risk group (scored 3–4) with a median PFS and OS of 3.1 months and 8.5 months respectively vs. not reached for patients scored 1–2. Combined with the ISS, the presence of >3 FLs on PET could improve the risk stratification of RRMM patients. Although anti-CD38 monoclonal antibodies have improved the prognosis of relapsed/refractory multiple myeloma (RRMM), some patients still experience early relapses with poor outcomes. This present study evaluated the predictive value of FDG PET/CT parameters for RRMM prior to initiating anti-CD38 treatment. We included 38 consecutive RRMM patients who underwent a PET/CT scan treated at our institution at relapse. The median PFS was 12.5 months and the median OS was not reached. 42% of the patients had an initial ISS score of 1, 37% of 2, and 21% of 3. The presence of >3 focal lesions (FLs, n = 19) and the ISS score were associated with inferior PFS (p = 0.0036 and p = 0.0026) and OS (p = 0.025 and p = 0.0098). Patients with >3 FLs had a higher initial ISS score (p = 0.028). In multivariable analysis, the ISS score and >3 FLs were independent prognostic factors for PFS (p = 0.010 and p = 0.025 respectively), and combined they individualized a high-risk group with a median PFS and OS of 3.1 months and 8.5 months respectively vs. not reached for the other patients. The presence of >3 FLs on PET was predictive of survival outcomes in patients with RRMM treated using CD38 targeted therapy. Combined with the initial ISS, an ultra-high-risk RRMM population can thus be identified. [ABSTRACT FROM AUTHOR]

Bispecific antibodies (Bs-Abs) containing an anti-CD3 and an anti-TAA specificity can recruit T cells to the tumor for cancer immunotherapy. To be effective, efficient activation at the tumor site is a prerequisite. This can be achieved by triggering both the T-cell receptor and the co-stimulatory molecule CD28. We engineered two recombinant cross-interacting Bs-Abs (CriBs-Abs) by incorporating a peptide tag and its cognate single-chain variable fragment (scFv), respectively, into a pair of (tumor × CD3) and (tumor × CD28) binding Bs-Abs. A 30-fold lower concentration of the activating CriBs-Ab as compared to non interacting Bs-Ab was sufficient for strong T-cell activation in the presence of tumor cells. One thousand-fold higher concentrations of both CriBs-Abs were required for marginal T-cell activation (70-fold below maximal response) in the absence of tumor cells. An optimized stoichiometry (1 : 1000) of activating versus co-stimulating CriBs-Ab thus allowed low doses of activating CriBs-Ab to induce tumor-cell dependent T-cell activation when used in combination with high concentrations of the pre-targeted co-stimulating CriBs-Ab in vitro. This indicates a large window of operation in which only tumor cell dependent T-cell activation is induced and systemic tumor cell independent T-cell activation is avoided, while ensuring optimal activation with a low concentration of the activating CriBs-Ab, which has the highest potential to induce toxic effects in vivo. [ABSTRACT FROM AUTHOR]

Sera from two groups of patients receiving grass pollen immunotherapy were tested on IgG reactivity with group V allergen from six different grass species. One group of patients was treated with a mixture of 10 grass species, and the other with a mixture of five. Only Lolium perenne, Dactylis glomerata, and Phleum pratense were present in both mixtures. Although Anthoxanthum odoratum and Secale cereale were absent from the mixture of five. IgG responses to Ant o V and Sec c V were comparable in both patient groups. This reactivity was inhibited for 92-99% with L. perenne extract, illustrating the cross-reactive nature of the IgG antibodies. The presence of A. odoratum and S. cereale in the mixture resulted in only minor amounts of species-specific anti-group V IgG. These results indicate that application of just one grass species in immunotherapy might be sufficient to induce an IgG response that covers other relevant Gramineae species as well. [ABSTRACT FROM AUTHOR]

Background: Ligands for the Toll-like receptor (TLR) family can induce activation of cells of the innate immune system and are widely studied for their potential to enhance adaptive immunity. Conjugation of TLR2-ligand Pam3CSK4 to synthetic long peptides (SLPs) was shown to strongly enhance the induction of antitumor immunity. To further improve cancer vaccination, we have previously shown that the novel TLR2-L Amplivant (AV), a modified Pam3CSK4, potentiates the maturation effects on murine DCs. In the current study, we further assessed the immunological properties of AV. Methods: Naïve mice were vaccinated with a conjugate of either Pam3CSK4 or AV and an SLP to assess specific T cell priming efficiency in vivo. The potency of AV and Pam3CSK4, either as free compounds or conjugated to different SLPs, to mature murine DCs was compared by stimulating murine dendritic cells overnight followed by ELISA and flow cytometry analysis. Murine tumor experiments were carried out by vaccinating mice carrying established HPV16 E6 and E7-expressing tumors and subsequently analyzing myeloid and lymphoid cells infiltrating the tumor microenvironment. Furthermore, tumor outgrowth after vaccination was monitored to enable comparison of the efficiency to induce antitumor immunity by Pam3CSK-SLP and AV-SLP conjugates. To enhance therapeutic efficacy, AV-SLP conjugate vaccination was combined with ablative therapies to assess whether synergism between such therapies would occur. Results: SLPs conjugated to AV induce stronger DC maturation, in vivo T cell priming and antitumor immunity compared to conjugates with Pam3CSK4. Interestingly, AV-SLP conjugates modulate the macrophage populations in the tumor microenvironment, correlating with a therapeutic effect in an aggressive murine tumor model. The potency of AV-SLP conjugates in cancer vaccination operates optimally in combination with chemotherapy or photodynamic therapy. Conclusion: These data allow further optimization of vaccination-based immunotherapy of cancer by use of the improved TLR2-ligand Amplivant. [ABSTRACT FROM AUTHOR]

Collagens are a primary component of the extracellular matrix and are functional ligands for the inhibitory immune receptor leukocyte-associated immunoglobulin-like receptor (LAIR)-1. LAIR-2 is a secreted protein that can act as a decoy receptor by binding collagen with higher affinity than LAIR-1. We propose that collagens promote immune evasion by interacting with LAIR-1 expressed on immune cells, and that LAIR-2 releases LAIR-1-mediated immune suppression. Analysis of public human datasets shows that collagens, LAIR-1 and LAIR-2 have unique and overlapping associations with survival in certain tumors. We designed a dimeric LAIR-2 with a functional IgG1 Fc tail, NC410, and showed that NC410 increases human T cell expansion and effector function in vivo in a mouse xenogeneic-graft versus-host disease model. In humanized mouse tumor models, NC410 reduces tumor growth that is dependent on T cells. Immunohistochemical analysis of human tumors shows that NC410 binds to collagen-rich areas where LAIR-1+ immune cells are localized. Our findings show that NC410 might be a novel strategy for cancer immunotherapy for immune-excluded tumors. [ABSTRACT FROM AUTHOR]

This multicenter Phase I study (NCT03585465) evaluated nivolumab in combination with 3 metronomic chemotherapy (MC) regimens in children with refractory/relapsing solid tumors. Objectives : To evaluate the feasibility and safety of the three regimens Patients aged < 18 years were enrolled. Nivolumab was combined with cyclophosphamide and vinblastine (arm A), capecitabine (arm B), or cyclophosphamide, vinblastine and capecitabine (arm C). Arm A and B were allocated sequentially. Arm C opened only if A and B were deemed safe. Dose-limiting toxicities (DLTs) were evaluated over the first two cycles. Patients were evaluable if they received > 2 cycles and > 70% of the planned dose. Sixteen patients were enrolled, 3 in arm A, 6 in arm B, and 7 in arm C. Median age was 11.5 years (range, 5–19). Patients previously received a median of 3.5 (range, 1–4) lines of systemic treatment, 14 patients had surgery and 11 had radiotherapy. Median number of cycles was 2 (1−24), median treatment duration was 56 days (18−714). In arm C, median number of cycles was 4 with median treatment duration of 95 days. No DLT was observed. Grade 3 adverse events (AE) and serious AE were observed in 8 patients (50%) and 1 patient (6%), respectively, over the first 2 cycles. No grade 4 AE occurred. The 6-month PFS and OS were 12% and 44%, respectively, in the whole population. Prolonged stable disease was observed in a high-grade glioma and an atypical teratoid rhabdoid tumor. Arm C appears safe. A randomized phase II trial evaluating the addition of nivolumab to the triple MC is ongoing. • The safety of new metronomic regimen associated with nivolumab have been evaluated. • The combinations of metronomic regimens and nivolumab appear safe with no observed DLT. • Long term disease control has been observed in patients with high grade glioma and ATRT. • A randomized phase 2 trial is evaluating the addition of nivolumab to the metronomic regimen. [ABSTRACT FROM AUTHOR]

Background: Peripheral T-cell lymphoma (PTCL) remains a therapeutic challenge. Due to the rarity and the heterogeneity of PTCL, no consensus has been achieved regarding even the type of first-line treatment. The benefit of autologous stem-cell transplantation (ASCT) is, therefore, still intensely debated. Patients and methods: In the absence of randomized trials addressing the role of ASCT, we performed a large multicentric retrospective study and used both a multivariate proportional hazard model and a propensity score matching approach to correct for sample selection bias between patients allocated or not to ASCT in intention-to-treat (ITT). Results: Among 527 patients screened from 14 centers in France, Belgium and Portugal, a final cohort of 269 patients ≤65 years old with PTCL-not otherwise specified (NOS) (N=78, 29%), angioimmunoblastic T-cell lymphoma (AITL) (N=123, 46%) and anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK-ALCL) (N=68, 25%) with partial (N=52, 19%) or complete responses (N=217, 81%) after induction was identified and information about treatment allocation was carefully collected before therapy initiation from medical records. One hundred and thirty-four patients were allocated to ASCT in ITT and 135 were not. Neither the Cox multivariate model (HR=1.02; 95% CI: 0.69-1.50 for PFS and HR=1.08; 95% CI: 0.68- 1.69 for OS) nor the propensity score analysis after stringent matching for potential confounding factors (logrank P=0.90 and 0.66 for PFS and OS, respectively) found a survival advantage in favor of ASCT as a consolidation procedure for patients in response after induction. Subgroup analyses did not reveal any further difference for patients according to response status, stage disease or risk category. Conclusions: The present data do not support the use of ASCT for up-front consolidation for all patients with PTCL-NOS, AITL, or ALK-ALCL with partial or complete response after induction. [ABSTRACT FROM AUTHOR]

Objectives: The programmed cell death-ligand 1 (PD-L1) 22C3 pharmDx assay is used as a companion diagnostic test to select head and neck squamous cell carcinoma (HNSCC) patients that may benefit from treatment with the checkpoint inhibitor pembrolizumab. Because the Dako platform is not universally available, we studied the performance of a 22C3 laboratory developed test (LDT) performed on a Ventana BenchMark Ultra compared to the 22C3 pharmDx assay.Materials and Methods: Serial sections from tissue micro arrays (TMAs) containing tumour tissue from 97 HNSCC patients were stained with the 22C3 pharmDx assay and 22C3 LDT. All TMA cores were scored by three dedicated head and neck pathologists for PD-L1 expression.Results: Substantial interobserver agreement was reported for both the standardized 22C3 pharmDx assay and the 22C3 LDT (respectively Fleiss' κ 0.62, 95% CI 0.57-0.67 and 0.63, 95% CI 0.58-0.68). Concordance between the assays was almost perfect on core and patient level (respectively Weighted κ 0.84, 95% CI 0.79-0.89 and 0.84, 95% CI 0.75-0.92). Intratumor heterogeneity between the cores per patient case was similar in both assays.Conclusion: After validation a 22C3 LDT is non-inferior to the standardized 22C3 pharmDx assay and can be safely used to select HNSCC patients for pembrolizumab treatment. [ABSTRACT FROM AUTHOR]