Evaluation of mycophenolic acid exposure in a patient with immune-related hepatotoxicity caused by nivolumab and ipilimumab therapy for malignant melanoma: a case report.

BACKGROUND: Guidelines such as the National Comprehensive Cancer Network recommend mycophenolate mofetil (MMF) for the treatment of severe steroid-refractory immune-related hepatotoxicity. Mycophenolic acid (MPA) is an active form of MMF that suppresses T- and B-lymphocyte proliferation and immune-related adverse events caused by immune checkpoint inhibitors. MPA has a narrow therapeutic range (37-70 µg·h/mL) and overexposure increases the risk of leukopenia in transplantation. However, the optimal use of MMF in oncology has not yet been established; thus, monitoring plasma MPA concentrations is necessary to avoid excessive immunosuppression in oncology practice. CASE PRESENTATION: We evaluated plasma MPA concentration in a 75-year-old man with immune-related hepatotoxicity following nivolumab and ipilimumab combination therapy for malignant melanoma. The patient developed severe hepatotoxicity after immunotherapy, and immunosuppressant therapy with corticosteroids was initiated. The patient then developed steroid-refractory immune-related hepatotoxicity; therefore, MMF (1,000 mg twice daily) was co-administered. Seven days after the administration of MMF, the plasma MPA concentration was measured using an enzyme multiplied immunoassay technique. The area under the plasma concentration-time curve for MPA from 0 to 12 h was 41.0 µg·h/mL, and the same dose of MMF was continued. Grade 2 lymphocytopenia, which could be attributed to MMF, was observed during the administration period. Unfortunately, the patient was infected with SARS-CoV-2 and died from respiratory failure. CONCLUSION: Our patient did not exceed the upper limit of MPA levels as an index of the onset of side effects of kidney transplantation and achieved rapid improvement in liver function. Prompt initiation of MMF after assessment of the steroid effect leads to adequate MPA exposure. Therapeutic drug monitoring should be considered when MMF is administered, to avoid overexposure.

Incidence of diabetes mellitus in patients treated with immune checkpoint inhibitors (ICI) therapy - A comprehensive cancer center experience.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and more patients are receiving ICIs than before. Although this has improved cancer care but so has the increase in the incidence of immune-related adverse events (irAEs) including endocrinopathies. ICI-induced diabetes mellitus (DM) is a rare irAE with an approximate incidence of 1%. Due to paucity of data in literature about ICI-induced DM, we conducted a study to report the incidence and characteristics of new onset and worsening of DM in patients treated with ICIs. METHODS: We conducted a retrospective review of patients who received ICIs during 10-year period. We identified patients with newly diagnosed DM and worsening of preexisting DM. FINDINGS: Among 2,477 patients who received one or multiple ICIs, 14 patients developed new onset DM and 11 patients experienced worsening of pre-existing DM. Median time to new onset or worsening DM from ICI treatment initiation was âˆ¼ 12 weeks. Median hemoglobin A1c was 6.2% at baseline and 8.5% at the onset of ICI-induced DM. Seven patients presented with diabetes ketoacidosis (DKA), all in the new onset group. (p = 0.02) No significant difference was observed between two groups regarding personal history of autoimmune disorder or family history of DM. (p greater than 0.05) Positive autoantibodies were found in three patients [two with Glutamic Acid Decarboxylase (GAD65) antibodies and one with insulin autoantibodies (IAA)]. INTERPRETATION: The incidence of new onset and worsening DM in patients treated with ICIs was 1.01%.

Outcomes of responders to PD-1/PD-L1 inhibitors who discontinue therapy after sustained disease control.

BACKGROUND: PD-1/PD-L1 immune checkpoint inhibitors (ICIs) are widely used in the treatment of metastatic malignancies. Judiciously balancing disease control (DC) against development of immune-related adverse events (irAE) remains a crucial aspect of treatment. The effect of treatment discontinuation after sustained disease control (SDC) is unknown. The purpose of this analysis was to evaluate outcomes of responders to ICI who discontinue treatment after a minimum of 12 months (SDC). METHODS: We retrospectively reviewed the database of the University of New Mexico Comprehensive Cancer Center (UNMCCC) between 2014 and 2021 and identified patients who had received ICI. Patients with metastatic solid tumors who had stopped ICI therapy after achieving SDC [stable disease, partial response, complete response (SD, PR, CR)] were selected and outcomes reviewed from their electronic health records. RESULTS: We identified 204 patients who were treated with ICI for various solid cancers. Forty-four patients (21.6%) met the criteria, of whom 35 with follow-up data were included in the final analysis; including 11 melanoma, 5 non-small cell lung, 4 head & neck, 8 renal, 4 urothelial, 1 anal, 1 Merkel cell carcinoma, and 1 liposarcoma. Patients were divided into two groups: those who stopped ICI due to an irAE [irAE group, n = 14, median treatment time (MTT), 16.6 mo] and those who stopped due to other reasons (eg completion of 2 years of therapy, n = 20, non-cancer related surgery, n = 1) (non-irAE group, n = 21, MTT, 23.7 mo). Among the irAE group, the most common irAE included pneumonitis, rash, transaminitis, and fatigue. As of data cutoff date, 9 of 14 (64%) patients continued to show SDC. Only 5 of 14 (36%) patients in this group experienced progression of disease (PD), with 1 of 2 patients achieving DC (median follow-up of 19.2 mo after last dose of treatment, range 3-50.2 mo). Among the non-irAE group, 13 of 21 (62%) continued to have SDC. Eight of 21 (38%) experienced PD after stopping treatment, 7 of whom received ICI rechallenge, with 2 of 7 achieving DC (median follow-up of 22.2 mo, range 3.6-54.8 mo). At a median follow-up of 21.3 mo from stopping ICI therapy (range, 3-54.8 mo), 10 patients (71%) from the irAE group and 13 (61.9%) from the non-irAE group are in DC and have not experienced PD. CONCLUSIONS: We demonstrate that 22 (66%) patients experienced SDC, regardless of cancer type or development of irAE. After including patients who were re-challenged with ICI due to PD, 25 (71%) remain in DC. Future prospective malignancy-specific trials are warranted to evaluate optimal treatment duration.

Successful treatment of immune-related lichenoid dermatitis by Weiling decoction in a patient with non-small cell lung cancer: A case report and review of literature.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have emerged as a revolutionary therapy in advanced squamous non-small cell lung cancer (sqNSCLC) and ushered a new era of immunotherapy. Despite of remarkable outcomes, a wide spectrum of immune-related adverse events (irAEs) was reported, among which cutaneous reactions were the most common. Cutaneous irAEs were mainly managed by glucocorticoids, whereas prolonged use of glucocorticoids may cuase kinds of side effects, especially in elderly paitients, and diminish the anti-tumor efficacy of ICIs, thus finding a safe and effective alternative approach to managing cutaneous irAEs is imperative. CASE SUMMARY: A 71-year-old man who was diagnosed with advanced sqNSCLC suffered from sporadic maculopapulars one week later after the fifth cycle of sintilimab treatment, and the skin lesions had been deteriorating rapidly. Skin biopsy revealed epidermal parakeratosis with a dense band-like lymphocytic infiltrate and acanthosis, indicating a diagnosis of immune-induced lichenoid dermatitis. Oral administration of traditional Chinese herbal formula modified Weiling decoction significantly alleviated the symptoms of the patient. The dosage of Weiling decoction were maintained for about three months without recurrence of cutaneous adverse reactions and any other side effects. The patient refused to receive further anti-tumor medication and stayed alive without disease progression at follow up. CONCLUSION: We present modified Weiling decoction successfully ameliorates immune-induced lichenoid dermatitis in a patient with sqNSCLC for the first time. This report indicates that Weiling decoction may be an effective and safe complementary or alternative approach for the treatment of cutaneous irAEs. Further investigation of the underling mechanism is required in the future.

Clinical outcomes by infusion timing of immune checkpoint inhibitors in patients with advanced non-small cell lung cancer.

BACKGROUND: We aimed to determine whether immune checkpoint inhibitors (ICI) time-of-day infusion might influence the survival of patients with advanced non-small cell lung cancer (NSCLC). METHODS: We retrospectively analysed patients who received single-agent anti-PD-(L)1 therapy in any line between 2016 and 2021. We calculated by Cox regression models the association between the proportion of ICI infusions received after 16:30h and overall survival (OS) and progression-free survival (PFS). RESULTS: 180 patients were included, 77% received ICI as second- or further-line (median of 12 infusions/patient). The median age was 65 years (IQR 57-70), 112 patients (62%) were male, 165 (92%) were current or former tobacco smokers, 140 (78%) had performance status (PS) 0 or 1, 26 (14%) were on steroid therapy at ICI initiation. Histology was non-squamous for 139 (77%), the median number of metastatic sites was 3, and 33% had brain metastases. Patients who received at least 20% of ICI infusions after 16:30h (65 out of 180, 36%) had a statistically significant shorter median PFS as compared with patients receiving less than 20% of infusions in the evening (4.9 vs 9.4 months, log-rank p = 0.020), while numerical but not statistical shorter OS was observed (14.0 vs 26.2 months, log-rank p = 0.090). In the multivariate analysis, receiving at least 20% of evening infusions did not significantly increase the risk of death, while PS and line of treatment were significantly correlated with the OS. On the contrary, a proportion of ICI administration after 16:30h ≥20% conferred an HR for the PFS of 1.44 (95% CI: 1.01-2.05, p = 0.043), but this prognostic effect was not found when including in the model the total number of ICI infusions received (HR 1.20, 95% CI: 0.83-1.75, p = 0.329). CONCLUSION: Time-of-day infusion of ICI may impact the survival of patients with advanced NSCLC. Underlying prognostic characteristics and the number of infusions received could represent conceivable confounding factors, linked to increased variance related to ICI infusion timing. Nonetheless, further studies may unravel chronobiological mechanisms modulating ICI efficacy.

Immune checkpoint inhibitor-mediated colitis is associated with cancer overall survival.

BACKGROUND: Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event following immune checkpoint inhibitor (ICI) therapy for cancer. IMC has been associated with improved overall survival (OS) and progression-free survival (PFS), but data are limited to a single site and predominantly for melanoma patients. AIM: To determine the association of IMC with OS and PFS and identify clinical predictors of IMC. METHODS: We performed a retrospective case-control study including 64 ICI users who developed IMC matched according to age, sex, ICI class, and malignancy to a cohort of ICI users without IMC, from May 2011 to May 2020. Using univariate and multivariate logistic regression, we determined association of presence of IMC on OS, PFS, and clinical predictors of IMC. Kaplan-Meier curves were generated to compare OS and PFS between ICI users with and without IMC. RESULTS: IMC was significantly associated with a higher OS (mean 24.3 mo vs 17.7 mo, P = 0.05) but not PFS (mean 13.7 mo vs 11.9 mo, P = 0.524). IMC was significantly associated with OS greater than 12 mo [Odds ratio (OR) 2.81, 95% confidence interval (CI) 1.17-6.77]. Vitamin D supplementation was significantly associated with increased risk of IMC (OR 2.48, 95%CI 1.01-6.07). CONCLUSION: IMC was significantly associated with OS greater than 12 mo. In contrast to prior work, we found that vitamin D use may be a risk factor for IMC.

Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer.

BACKGROUND: Neoadjuvant or adjuvant chemotherapy confers a modest benefit over surgery alone for resectable non-small-cell lung cancer (NSCLC). In early-phase trials, nivolumab-based neoadjuvant regimens have shown promising clinical activity; however, data from phase 3 trials are needed to confirm these findings. METHODS: In this open-label, phase 3 trial, we randomly assigned patients with stage IB to IIIA resectable NSCLC to receive nivolumab plus platinum-based chemotherapy or platinum-based chemotherapy alone, followed by resection. The primary end points were event-free survival and pathological complete response (0% viable tumor in resected lung and lymph nodes), both evaluated by blinded independent review. Overall survival was a key secondary end point. Safety was assessed in all treated patients. RESULTS: The median event-free survival was 31.6 months (95% confidence interval [CI], 30.2 to not reached) with nivolumab plus chemotherapy and 20.8 months (95% CI, 14.0 to 26.7) with chemotherapy alone (hazard ratio for disease progression, disease recurrence, or death, 0.63; 97.38% CI, 0.43 to 0.91; P = 0.005). The percentage of patients with a pathological complete response was 24.0% (95% CI, 18.0 to 31.0) and 2.2% (95% CI, 0.6 to 5.6), respectively (odds ratio, 13.94; 99% CI, 3.49 to 55.75; P<0.001). Results for event-free survival and pathological complete response across most subgroups favored nivolumab plus chemotherapy over chemotherapy alone. At the first prespecified interim analysis, the hazard ratio for death was 0.57 (99.67% CI, 0.30 to 1.07) and did not meet the criterion for significance. Of the patients who underwent randomization, 83.2% of those in the nivolumab-plus-chemotherapy group and 75.4% of those in the chemotherapy-alone group underwent surgery. Grade 3 or 4 treatment-related adverse events occurred in 33.5% of the patients in the nivolumab-plus-chemotherapy group and in 36.9% of those in the chemotherapy-alone group. CONCLUSIONS: In patients with resectable NSCLC, neoadjuvant nivolumab plus chemotherapy resulted in significantly longer event-free survival and a higher percentage of patients with a pathological complete response than chemotherapy alone. The addition of nivolumab to neoadjuvant chemotherapy did not increase the incidence of adverse events or impede the feasibility of surgery. (Funded by Bristol Myers Squibb; CheckMate 816 ClinicalTrials.gov number, NCT02998528.).

Immunological and nutritional predictive factors in patients receiving pembrolizumab for the first-line treatment of non-small cell lung cancer.

PURPOSE: Immune checkpoint inhibitors (ICIs) have prolonged the survival of patients with various carcinomas, including non-small cell lung cancer (NSCLC), and have caused a paradigm shift in cancer treatment. Although programmed death-ligand 1 (PD-L1) expression in tumor cells is a predictive marker of therapeutic efficacy, additional predictive markers are required. This study aimed to explore the role of immunological and nutritional parameters in the prediction of treatment response. METHODS: Patients diagnosed with NSCLC and treated with pembrolizumab were examined retrospectively. Body weight was measured 4-6 weeks before the start of the first treatment, immediately before treatment, and 4-6 weeks after the start of the first treatment. Progression-free survival (PFS) was defined as the time from the start of pembrolizumab treatment to the last follow-up date or until disease progression. Statistical analyses were performed to confirm the association between various factors and association between these factors and PFS. RESULTS: Thirty-eight patients with advanced NSCLC were included. We observed a significant association of weight loss and PD-L1 expression with PFS in the multivariate analysis. A significant correlation was found between the advanced lung cancer inflammation index and neutrophil-to-lymphocyte ratio. A weight loss of > 5% after the start of treatment was significantly associated with worse PFS. CONCLUSIONS: Weight loss is an important negative prognostic factor in patients with NSCLC receiving immunotherapy. Weight maintenance may be important for good ICI treatment efficacy, and future interventions in cancer cachexia are expected to further enhance the treatment efficacy of ICIs.

Inhibitors of immune checkpoints-PD-1, PD-L1, CTLA-4-new opportunities for cancer patients and a new challenge for internists and general practitioners.

The treatment of cancer patients with immune checkpoint inhibitors (ICI) (anti-CTLA-4, anti-PD-1, anti-PD-L1, combined therapy anti-PD-1/PD-L1 with anti-CTLA-4) has without doubt been a significant breakthrough in the field of oncology in recent years and constitutes a major step forward as a novel type of immunotherapy in the treatment of cancer. ICIs have contributed to a significant improvement in the outcome of treatment and prognosis of patients with different types of malignancy. With the expansion of the use of ICIs, it is expected that caregivers will face new challenges, namely, they will have to manage the adverse side effects associated with the use of these drugs. New treatment options pose new challenges not only for oncologists but also for specialists in other clinical fields, including general practitioners (GPs). They also endorse the need for taking a holistic approach to the patient, which is a principle widely recognized in oncology and especially relevant in the case of the expanding use of ICIs, which may give rise to a wide variety of organ complications resulting from treatment. Knowledge and awareness of the spectrum of immune-related adverse events (irAEs) will allow doctors to qualify patients for treatment more appropriately, prevent complications, correctly recognize, and ultimately treat them. Additionally, patients with more non-specific symptoms would be expected, in the first instance, to consult their general practitioners, as complications may appear even after the termination of treatment and do not always proceed in line with disease progression. Dealing with any iatrogenic complications, will not only be the remit of oncologists but because of the likelihood that specific organs may be affected, is likely to extend also to specialists in various fields of internal medicine. These specialists, e.g., endocrinologists, dermatologists, pulmonologists, and gastroenterologists, are likely to receive referrals for patients suffering from specific types of adverse events or will be asked to provide care in cases requiring hospitalization of patients with complications in their field of expertise. In view of these considerations, we believe that there is an urgent need for multidisciplinary teamwork in the treatment of cancer patients undergoing immunotherapy and suffering the consequent adverse reactions to treatment.

Calcitriol-mediated hypercalcemia as an immune-related adverse event in a patient receiving nivolumab and ipilimumab for metastatic renal cell carcinoma, case report.

BACKGROUND: Severe hypercalcemia is often associated with uncontrolled malignancy through several mechanisms. However, calcitriol-mediated hypercalcemia is a rare etiology for advanced solid tumors. CASE PRESENTATION: We report a case of calcitriol-mediated hypercalcemia secondary to immune checkpoint inhibition in a responder with metastatic clear cell renal cell carcinoma (ccRCC). In this case, a 68 year old male with metastatic ccRCC to the liver within 4 months of right radical nephrectomy went on to develop hypercalcemia (12.8 mg/dL) shortly following 2 cycles of nivolumab and ipilimumab. Additional testing showed an elevated calcitriol level (142 pg/mL), low parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) levels, and a normal 25-hydroxyvitamin D level. FDG-PET imaging showed hypermetabolic mediastinal, hilar, and intra-abdominal lymphadenopathy, however the subsequent lymph node biopsy only showed reactive lymphoid cells without malignancy or granuloma. The hypercalcemia was resistant to initial therapy with calcitonin, hydration, and zoledronic acid but quickly responded to high-dose prednisone (1 mg/kg), followed by normalization of calcitriol levels. The patient was rechallenged with nivolumab and ipilimumab which provided a partial response after 4 cycles. He was maintained on low dose prednisone (10 mg daily) leading to a sustained resolution of his hypercalcemia. CONCLUSION: This case suggests calcitriol-mediated hypercalcemia as a novel immune-related adverse event.

Quantitative Clinical Pharmacology of T-Cell Engaging Bispecifics: Current Perspectives and Opportunities.

T-cell directing/engaging bispecifics (TDBs) enable a powerful mode of action by activating T-cells through the creation of artificial immune synapses. Their pharmacological response involves the dynamic inter-relationships among T-cells, tumor cells, and TDBs. This results in complex and challenging issues in understanding pharmacokinetics, tissue distribution, target engagement, and exposure-response relationship. Dosing strategy plays a crucial role in determining the therapeutic window of TDBs because of the desire to maximize therapeutic efficacy in the context of known mechanism-related adverse events, such as cytokine release syndrome and neurological adverse events. Such adverse events are commonly reported as the most prominent events during the initial treatment cycles and dissipate over time. Therefore, the kinetic characterization of the inter-relationships between exposure/target engagement and safety/efficacy outcomes is crucial in designing the optimal dosing regimen to maximize the benefit/risk of TDB agents. In this review, we discuss the key clinical pharmacological considerations in drug discovery and development for TDBs and provide a summary of TDBs currently in clinical development. We also propose forward-looking perspectives and opportunities to derive insights through quantitative clinical pharmacology approaches.

Gemtuzumab ozogamicin in acute myeloid leukemia: past, present and future.

After being in the therapeutic wilderness for several decades, acute myeloid leukemia has been recently thrust into the limelight with a series of drug approvals. Technical refinements in production, genetic manipulation and chemical modification of monoclonal antibodies led to growing interest in antibodies-based treatment strategies. Much of the focus of these efforts in acute myeloid leukemia has been on CD33 as a target. On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin for treatment of relapsed or refractory CD33+ acute myeloid leukemia. This signals a new chapter in the long and unusual story of gemtuzumab ozogamicin, which was the first antibody-drug conjugate approved for human use by the Food and Drug Administration. In this review we have analyzed the history of this drug which, among several mishaps, is experiencing a second youth and still represents a field to be further explored.

Maintenance rituximab in Veterans with follicular lymphoma.

Real-world practice patterns and clinical outcomes in patients with follicular lymphoma (FL), including the adoption of maintenance rituximab (MR) therapy in the United States (US), have been reported in few studies since the release of the National LymphoCare Study almost a decade ago. We analyzed data from the largest integrated healthcare system in the United States, the Veterans Health Administration (VHA), to identify rates of adoption and effectiveness of MR in FL patients after first-line (1L) treatment. We identified previously untreated patients with FL in the VHA between 2006 and 2014 who achieved at least stable disease after chemoimmunotherapy or immunotherapy. Among these patients, those who initiated MR within 238 days of 1L composed the MR group, whereas those who did not were classified as the non-MR group. We examined the effect of MR on progression-free survival (PFS) and overall survival (OS). A total of 676 patients met our inclusion criteria, of whom 300 received MR. MR was associated with significant PFS (hazard ratio [HR]=0.55, P < .001) and OS (HR = 0.53, P = .005) compared to the non-MR group, after adjusting by age, sex, ethnicity, geographic region, diagnosis period, stage, grade at diagnosis, hemoglobin, lactate dehydrogenase (LDH), Charlson comorbidity index (CCI), 1L treatment regimen, and response to 1L treatment. These results suggest that in FL patients who do not experience disease progression after 1L treatment in real-world settings, MR is associated with a significant improvement in both PFS and OS. Maintenance therapy should be considered in FL patients who successfully complete and respond to 1L therapy.

Severe chronic nonlichenoid oral mucositis in pembrolizumab-treated patients: new cases and a review of the literature.

Aim: To report of severe chronic oral mucositis (OM) in two pembrolizumab-treated cancer patients. Materials & methods: A retrospective chart review was performed. Inclusion/exclusion criteria detected patients that developed OM during pembrolizumab immunotherapy. In addition, we searched the literature for nonlichenoid OM in immunotherapy-treated cancer patients. Results: Two male patients treated for anaplastic astrocytoma and lung adenocarcinoma were included. Extensive painful OM (grade 4) developed in both patients during the course of immunotherapy and the ulcerations remained >30 weeks (>16 weeks after stopping immunotherapy). Superficial mucocele appeared in one patient. In one patient, pain relief was achieved with photobiomodulation (low-level laser) therapy. Conclusion: OM induced by immunotherapy may be a major cause of suffering and eating difficulties. In most cases, the OM lasted for months even after the drug was stopped. There is a controversy regarding the beneficial effect of corticosteroids on OM in these patients.

Prognostic impact of immune-microenvironment in colorectal liver metastases resected after triplets plus a biologic agent: A pooled analysis of five prospective trials.

BACKGROUND: Immune-contexture of tumour microenvironment (TME) influences prognosis of colorectal cancer (CRC) patients and can be altered by cytotoxic and targeted agents. Limited data are available regarding the immune-TME of CRC after treatment. METHODS: An extensive immunohistochemistry evaluation of immunological parameters on tumour cells and TME of colorectal liver metastases from 106 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (5-fluorouracil, oxaliplatin and irinotecan) or COI (capecitabine, oxaliplatin and irinotecan) plus bevacizumab (N = 59) or cetuximab (N = 47) in five first-line no-profit clinical trials was performed. RESULTS: No substantial differences were reported in immunological parameters according to administered targeted agent, RAS/BRAF mutational status and histopathological or Response Evaluation Criteria in Solid Tumours response. Stromal expression of Cyclooxygenase-2 (COX-2) (p = 0.002), Human leukocyte antigen (HLA) (p = 0.003) and Programmed cell death protein 1 (PD1) (p = 0.002) were independent prognostic factors for longer relapse-free survival (RFS) at multivariate analysis with a positive trend for post-resection overall survival (OS). Patients whose metastases expressed stromal COX-2, HLA and PD1 (inflamed-score positive) reported longer RFS (25.5 versus 9.8 months; p < 0.001) and post-resection OS (64.3 versus 37.7 months; p = 0.003) as compared with others. In addition, patients with higher expression of CD4 and CD8 T-cells in tumour core and invasive margin (CD4/CD8-score) showed a better post-resection OS (not-reached versus 41.6 months; p = 0.032). A combined score of inflamed-score and CD4/CD8-score (combo-score) showed a clear prognostic role. CONCLUSIONS: The present study emphasises the role of immune-TME as independent predictor of survival in patients resected after triplets plus biologic. Inflamed-, CD4/C8- and combo-scores should be confirmed as prognostic factors in further studies.

Systemic inflammatory response and nutritional biomarkers as predictors of nivolumab efficacy for gastric cancer.

PURPOSE: To investigate the usefulness of clinicopathological systemic inflammatory response and nutritional biomarkers for predicting the efficacy of nivolumab in patients with advanced gastric cancer. METHODS: The subjects of this study were 29 patients who received nivolumab treatment for advanced gastric cancer at the Kochi Medical School between 2017 and 2019. Clinicopathological information, including systemic inflammatory response data, were obtained to investigate the associations between baseline cancer-related prognostic variables and survival outcomes. RESULTS: Immune-related adverse events (irAEs) of any grade were identified in 34.5% (10/29) of the patients. The median progression-free survival of patients with irAEs was significantly greater than that of patients without irAEs (5.8 months vs. 1.2 months, respectively; P = 0.028). The neutrophil to lymphocyte ratio (NLR) after 4 weeks of treatment in the complete response (CR) or partial response (PR) group was significantly lower than that in the stable disease (SD) or progression disease (PD) group (2.2 vs. 2.9, respectively; P = 0.044). The prognostic nutrition index (PNI) before treatment in the CR or PR group was significantly higher than that in the SD or PD group (37.1 vs. 32.1, respectively; P = 0.011). The PNI 8 weeks after treatment and the Glasgow prognostic score (GPS) before treatment were significantly associated with a poor outcome. CONCLUSION: The irAE, NLR, PNI, and GPS may be useful predictive markers for nivolumab efficacy in patients with advanced gastric cancer.

Clinical and molecular insights into BCG immunotherapy for melanoma.

The incidence of cutaneous melanoma and the mortality rate of advanced melanoma patients continue to rise globally. Despite the recent success of immunotherapy including ipilimumab and pembrolizumab checkpoint inhibitors, a large proportion of patients are refractory to such treatment modalities. The application of mycobacteria such as Bacillus Calmette-Guérin (BCG) in the treatment of various malignancies, including cutaneous melanoma, has been clearly demonstrated after almost a century of observations and experimentation. Intralesional BCG (IL-BCG) immunotherapy is a highly efficient and cost-effective treatment option for inoperable stage III in-transit melanoma, as recommended in the National Comprehensive Cancer Network Guidelines. IL-BCG has shown great efficacy in the regression of directly injected metastatic melanoma lesions, as well as distal noninjected nodules in immunocompetent patients. Clinical and preclinical studies have shown that BCG serves as a strong immune modulator, inducing the recruitment of various immune cells that contribute to antitumour immunity. However, the specific mechanism of BCG-mediated tumour immunity remains poorly understood. Comparative genome analyses have revealed that different BCG strains exhibit distinct immunological activity and virulence, which might impact the therapeutic response and clinical outcome of patients. In this review, we discuss the immunostimulatory potential of different BCG substrains and highlight clinical studies utilizing BCG immunotherapy for the treatment of cutaneous melanoma. Furthermore, the review focuses on the cellular and molecular mechanisms of the BCG-induced immune responses of both the innate and adaptive arms of the immune system. Furthermore, the review discussed the administration of BCG as a monotherapy or in combination with other immunotherapeutic or chemotherapeutic agents.

Target-Mediated Drug Disposition Pharmacokinetic/Pharmacodynamic Model-Informed Dose Selection for the First-in-Human Study of AVB-S6-500.

AVB-S6-500 neutralized growth arrest-specific 6 (GAS6) protein and effectively inhibited AXL signaling in preclinical cancer models. A target-mediated drug disposition (TMDD) pharmacokinetic/pharmacodynamic (PK/PD) model was used to select first-in-human (FIH) doses for AVB-S6-500 based on predicted target (GAS6) suppression in the clinic. The effect of TMDD on AVB-S6-500 clearance was incorporated into a standard two-compartment model, providing parallel linear and nonlinear clearance. Observed AVB-S6-500 and GAS6 concentration data in cynomolgus monkeys and relevant interspecies differences were used to predict the PK (serum concentration)/PD (GAS6 suppression) relationship in humans. Human exposure and GAS6 suppression were simulated for the proposed FIH doses of 1, 2.5, 5, and 10 mg/kg. A dose of 1 mg/kg was selected to target GAS6 suppression for 2 weeks in the initial healthy volunteer study. The cynomolgus monkey:human ratios for the highest proposed FIH dose were anticipated to yield more than a 10-fold margin to the nonclinical no observed adverse event level while maintaining > 90% GAS6 suppression. In human subjects, the first dose (1 mg/kg) model-projected and clinically observed maximal concentration (Cmax ) was within 10% of predicted; repeat dosing at 5 mg/kg was within 1% (Cmax ) and 45% (area under the serum concentration-time curve from time 0 to end of dosing interval) of predicted. Predicted GAS6 suppression duration of 14 days was accurate for the 1 mg/kg dose. A PK/PD model expedited clinical development of AVB-S6-500, minimized exposure of patients with cancer to subtherapeutic doses, and rationally guided the optimal dosing in patients.

Evaluation of the MD Anderson tumor score for diffuse large B-cell lymphoma in the rituximab era.

OBJECTIVES: Diffuse large B-cell lymphoma (DLBCL) is an aggressive heterogeneous lymphoma with standard treatment. However, 30%-40% of patients still fail, so we should know which patients are candidates for alternative therapies. IPI is the main prognostic score but, in the rituximab era, it cannot identify a very high-risk (HR) subset. The MD Anderson Cancer Center reported a score in the prerituximab era exclusively considering tumor-related variables: Tumor Score (TS). We aim to validate TS in the rituximab era and to analyze its current potential role. METHODS: From GELTAMO DLBCL registry, we selected those patients homogeneously treated with R-CHOP (n = 1327). RESULTS: Five-years PFS and OS were 62% and 74%. All variables retained an independent prognostic role in the revised TS (R-TS), identifying four different risk groups, with 5-years PFS of 86%, 71%, 50%, and very HR (28%). With a further categorization of three variables of the original TS (Ann Arbor Stage, LDH and B2M), we generated a new index that allowed an improvement in HR assessment. CONCLUSIONS: (a) All variables of the original TS retain an independent prognostic role, and R-TS remains predictive in the rituximab era; (b) R-TS and additional categorization of LDH, B2M, and AA stage (enhanced TS) increased the ability to identify HR subsets.