Peripheral-immune-checkpoint blockade (P-ICB) with mAbs to PD-1 (nivolumab and pembrolizumab) or PD-L1 (atezolizumab, durvalumab, avelumab) alone or combination with chemotherapy represents a novel ...active treatment for mNSCLC patients. However, this therapy can be associated to immune-related adverse events (irAEs) and high cost. Therefore, finding reliable biomarkers of response and irAEs is strongly encouraged to accurately select patients who may potentially benefit from the immuno-oncological treatment. This is a retrospective multi-institutional analysis performed on ninety-five mNSCLC patients who received real-world salvage therapy with nivolumab or atezolizumab between December 2015 and April 2020. The outcome of these patients in term of PFS and OS was evaluated in comparison with different serum levels of C-reactive protein (CRP), Erythrocyte Sedimention Rate (ESR) and Procalcitonin (PCT) by performing Kaplan–Meier and Log-rank test and multivariate analysis. We found that high baseline levels of CRP, ESR, and PCT were strongly predictive of poor outcome (P <0.05) with the worse prognosis detected in those patients with a baseline levels of both ESR and PCT over the pre-established cut off (median OS recorded in patients with no marker over the cut off
vs
. those with just one marker over the cut off
vs
. those with both markers over the cut off: 40 ± 59
vs
. 15.5 ± 5.5
vs
. 5.5 ± 1.6 months, respectively; P <0.0001). Our results suggest the predictive value of systemic inflammation and suggest a potential role of PCT in predicting a poor outcome in mNSCLC receiving PD-1/PD-L1 blocking mAbs. This finding also suggests a potential role of subclinical bacterial infections in defining the response to PD-1/PD-L1 blocking mAbs that deserves further and more specific investigations.
Pembrolizumab (mAb to PD-1) has been recently approved for the therapy of pretreated urothelial cancer. Despite the efficacy, it is often accompanied by unpredictable and sometime severe ...immune-related (ir) adverse events (AEs). Here, we report the clinical and immune–biological characterization of a patient with a metastatic bladder cancer who developed myositis signs (M) and a myasthenia-like syndrome (MLS) during treatment with pembrolizumab. The patient presented an autoimmunity-associated HLA haplotype (HLA-A*02/HLA-B*08/HLA-C*07/HLA-DRB1*03) and experienced an increase in activated CD8 T-cells along the treatment. The symptomatology regressed after pembrolizumab discontinuation and a pyridostigmine and steroids-based therapy. This is the first report of concurrent M and MLS appearance in cancer patients receiving pembrolizumab. More efforts are needed to define early the risk and the clinical meaning of irAEs in this setting.
BackgroundNivolumab is a human monoclonal antibody against programmed cell death receptor-1 (PD-1) able to rescue quiescent tumor infiltrating cytotoxic T lymphocytes (CTLs) restoring their ability ...to kill target cells expressing specific tumor antigen-derived epitope peptides bound to homologue human leukocyte antigen (HLA) molecules. Nivolumab is currently an active but expensive therapeutic agent for metastatic non-small cell lung cancer (mNSCLC), producing, in some cases, immune-related adverse events (irAEs). At the present, no reliable biomarkers have been validated to predict either treatment response or adverse events in treated patients.MethodsWe performed a retrospective multi-institutional analysis including 119 patients with mNSCLC who received PD-1 blockade since November 2015 to investigate the predictive role of germinal class I HLA and DRB1 genotype. We investigated the correlation among patients’ outcome and irAEs frequency with specific HLA A, B, C and DRB1 alleles by reverse sequence-specific oligonucleotide (SSO) DNA typing.ResultsA poor outcome in patients negative for the expression of two most frequent HLA-A alleles was detected (HLA: HLA-A*01 and or A*02; progression-free survival (PFS): 7.5 (2.8 to 12.2) vs 15.9 (0 to 39.2) months, p=0.01). In particular, HLA-A*01-positive patients showed a prolonged PFS of 22.6 (10.2 to 35.0) and overall survival (OS) of 30.8 (7.7 to 53.9) months, respectively. We also reported that HLA-A and DRB1 locus heterozygosis (het) were correlated to a worse OS if we considered het in the locus A; in reverse, long survival was correlated to het in DRB1.ConclusionsThis study demonstrate that class I and II HLA allele characterization to define tumor immunogenicity has relevant implications in predicting nivolumab efficacy in mNSCLC and provide the rationale for further prospective trials of cancer immunotherapy.
Tumor-infiltrating T cell rescue by programmed cell death receptor-1 (PD-1)/PD-1 ligand-1 (PD-L1) immune checkpoint blockade is a recommended treatment for malignant diseases, including metastatic ...non-small-cell lung cancer (mNSCLC), malignant melanoma (MM), head and neck, kidney, and urothelial cancer. Monoclonal antibodies (mAbs) against either PD-1 or PD-L1 are active agents for these patients; however, their use may be complicated by unpredictable immune-related adverse events (irAEs), including immune-related pneumonitis (IRP). We carried out a retrospective multi-institutional statistical analysis to investigate clinical and biological parameters correlated with IRP rate on a cohort of 256 patients who received real-world treatment with PD-1/PD-L1 blocking mAbs. An independent radiological review board detected IRP in 29 patients. We did not find statistical IRP rate correlation with gender, tumor type, specific PD-1 or PD-L1 blocking mAbs, radiation therapy, inflammatory profile, or different irAEs. A higher IRP risk was detected only in mNSCLC patients who received metronomic chemotherapy +/- bevacizumab compared with other treatments prior PD-1/PD-L1 blockade. Moreover, we detected a strong correlation among the IRP rate and germinal expression of HLA-B*35 and DRB1*11, alleles associated to autoimmune diseases. Our findings may have relevant implications in predicting the IRP rate in mNSCLC patients receiving PD-1/PD-L1 blockade and need to be validated on a larger patient series.
An immune checkpoint blockade with mAbs to PD-1 and PD-L1 is an expanding therapeutic option for mNSCLC patients. This treatment strategy is based on the use of mAbs able to restore the anti-tumor ...activity of intratumoral T cells inhibited by PD-1 binding to PD-L1/2 on tumor and inflammatory cells. It has been speculated that a chronic status of systemic inflammation as well as the immunosenescence physiologically occurring in elderly patients may affect the efficacy of the treatment and the occurrence of irAEs. We performed a multi-institutional retrospective study aimed at evaluating the effects of these mAbs (nivolumab or atezolizumab) in 117 mNSCLC patients younger (90 cases) and older (27 cases) than 75 years in correlation with multiple inflammatory parameters (NLR, CRP, ESR, LDH and PCT). No differences were observed when the cohorts were compared in terms of the frequency of PFS, OS, inflammatory markers and immune-related adverse events (irAEs). Similarly, the occurrence of irAEs was strictly correlated with a prolonged OS survival in both groups. On the contrary, a negative correlation between the high baseline levels of inflammatory markers and OS could be demonstrated in the younger cohort only. Overall, PD-1/PD-L1-blocking mAbs were equally effective in young and elderly mNSCLC patients; however, the detrimental influence of a systemic inflammation at the baseline was only observed in young patients, suggesting different aging-related inflammation immunoregulative effects.
Immune-checkpoint blockade by Nivolumab, a human monoclonal antibody to programmed cell death receptor-1, is an emerging treatment for metastatic non-small cell lung cancer (mNSCLC). In order to ...prolong patient survival, this treatment requires a continuous cross-priming of tumor derived-antigens to supply fresh tumor-specific immune-effectors; a phenomenon that may also trigger auto-immune-related adverse events (irAEs). The present study therefore investigated the prognostic value of multiple autoimmunity-associated parameters in patients with mNSCLC who were undergoing Nivolumab treatment. This retrospective study included 92 mNSCLC patients who received salvage therapy with Nivolumab (3 mg/kg, biweekly) between September 2015 and June 2018. Log-rank test, Mantel-Cox and McPherson analyses were conducted to correlate patient progression-free survival (PFS) and overall survival (OS) with different parameters including blood cell counts, serum inflammatory markers and auto-antibodies (AAbs). A median PFS and OS of 10 inter-quartile range (IQR): 5.8-14.2 and 16 IQR: 6.2-25.8 months, respectively, were recorded, which did not correlated with age, histology or the number of previous chemotherapy lines. Male gender, the type of therapeutic regimens received prior to Nivolumab, and the occurrence of irAEs were revealed to be positive predictors of prolonged survival (P<0.05). Early detection (within 30 days) of >1AAbs among anti-nuclear antigens (ANAs), extractable nuclear antigens (ENAs) and anti-smooth cell antigens (ASMAs) correlated with prolonged PFS hazard ratio (HR)=0.23; 95% confidence interval (CI): 0.08-0.62; P=0.004 and OS HR=0.28 (95% CI: 0.09-0.88), P=0.03, with the type of treatment received prior to nivolumab (P=0.007) and with the risk of irAEs (P=0.002). In conclusion, increased serum levels of ANA, ENA and/or ASMA are consequential to Nivolumab administration and are predictive of a positive outcome in mNSCLC patients.
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Background: In the last few years, there has been a renewed interest on the potential use of immunotherapy alone or combined to chemotherapy (CHT) for mCRC patients. GOLFIG ...regimen (biweekly Gemcitabine+FOLFOX and IL2 and GM-CSF) was designed to enhance immunomodulating effects of selected cytotoxic drugs by combining them with cytokines able to promote priming and effector phases of the immune-response. This regimen has been tested in two different phase II and III clinical trials in mCRC patients, whose successful results have been published. Here we present the results a retrospective analyses including all the patients treated in a period of 16 years. Methods: This is a multi-institutional retrospective study including 179 mCRC patients (106 men, 73 women). They received a median of 12 courses of GOLFIG regimen (treated between June 2002 and November 2018). K-RAS mutational status has also been evaluated in 74 pts (41 wild type and 33 mutated); as for sidedness 112 pts had a left disease and 67 pts right disease; 71 pts received only one previous CHT line and 100 more than two lines. PFS and OS were evaluated by Kaplan-Meier curves and Cox-regression analyses in different subgroups (RAS mutational status, sidedness, previous CHT lines) to estimate their effect on survival endpoints. Results: We recorded a mean PFS and OS of 15,28 95%CI:10,36-20,20 and 24,61 95%CI:19,07-30,14 months, respectively, with no difference in efficacy outcomes observed among the different subgroups (one vs. more than one previous CHT lines; left vs. right primary side; k-ras status mutated vs. wt). Finally, we recorded a 2, 5 and 10 year OS-rate, in 42, 17 and 14 percent of the patients, respectively. The occurrence of self-limiting autoimmunity was confirmed as highly predictive of longer survival. Conclusions: These results confirm that GOLFIG regimen has strong efficacy in mCRC pts and may represent a reliable option in pretreated setting without evident effect of known prognostic variants. Such data offer a strong basis for future clinical trials in mCRC patients, where GOLFIG may represent a scaffold for combinatory immunotherapy approaches with immune-checkpoint blocking drugs.
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