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BACKGROUND: Recent studies indicate an association between immunosuppression for immune-related adverse events (irAEs) and impaired survival in patients who received immune checkpoint inhibitors. Whether this is related to corticosteroids or second-line immunosuppressants is unknown. In the largest cohort thus far, we assessed the association of immunosuppressant type and dose with survival in melanoma patients with irAEs. METHODS: Patients with advanced melanoma who received immunosuppressants for irAEs induced by first-line anti-PD-1 ± anti-CTLA-4 were included from 18 hospitals worldwide. Associations of cumulative and peak dose corticosteroids and use of second-line immunosuppression with survival from start of immunosuppression were assessed using multivariable Cox proportional hazard regression. RESULTS: Among 606 patients, 404 had anti-PD-1 + anti-CTLA-4-related irAEs and 202 had anti-PD-1-related irAEs. 425 patients (70 %) received corticosteroids only; 181 patients (30 %) additionally received second-line immunosuppressants. Median PFS and OS from starting immunosuppression were 4.5 (95 %CI 3.4-8.1) and 31 (95 %CI 15-not reached) months in patients who received second-line immunosuppressants, and 11 (95 %CI 9.4-14) and 55 (95 %CI 41-not reached) months in patients who did not. High corticosteroid peak dose was associated with worse PFS and OS (HRadj 1.14; 95 %CI 1.01-1.29; HRadj 1.29; 95 %CI 1.12-1.49 for 80vs40mg), while cumulative dose was not. Second-line immunosuppression was associated with worse PFS (HRadj 1.32; 95 %CI 1.02-1.72) and OS (HRadj 1.34; 95 %CI 0.99-1.82) compared with corticosteroids alone. CONCLUSIONS: High corticosteroid peak dose and second-line immunosuppressants to treat irAEs are both associated with impaired survival. While immunosuppression is indispensable for treatment of severe irAEs, clinicians should weigh possible detrimental effects on survival against potential disadvantages of undertreatment.
Subject(s)
Adrenal Cortex Hormones , Immune Checkpoint Inhibitors , Immunosuppressive Agents , Melanoma , Humans , Male , Female , Melanoma/drug therapy , Melanoma/immunology , Melanoma/mortality , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Immune Checkpoint Inhibitors/adverse effects , Middle Aged , Aged , Adrenal Cortex Hormones/therapeutic use , Adrenal Cortex Hormones/adverse effects , Adult , Retrospective Studies , Skin Neoplasms/drug therapy , Skin Neoplasms/immunology , Skin Neoplasms/mortality , Aged, 80 and overABSTRACT
INTRODUCTION: Severe immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICIs) can lead to admission to the intensive care unit (ICU). In this retrospective study, we determined the incidence, treatment patterns and survival outcomes of this patient population at a comprehensive cancer center. METHODS: All patients admitted to the ICU due to irAEs from ICI treatment between January 2015 and July 2022 were included. Descriptive statistics were reported on patient characteristics and treatment patterns during hospital admission. Overall survival (OS) from the time of ICU discharge to death was estimated using the Kaplan-Meier method. RESULTS: Over the study period, 5561 patients received at least one ICI administration, of which 32 patients (0.6%) were admitted to the ICU due to irAEs. Twenty patients were treated with anti-PD-1 plus anti-CTLA-4 treatment, whereas 12 patients were treated with ICI monotherapy. The type of irAEs were de novo diabetes-related ketoacidosis (n = 8), immune-related gastrointestinal toxicity (n = 8), myocarditis or myositis (n = 10), nephritis (n = 3), pneumonitis (n = 2), and myelitis (n = 1). The median duration of ICU admission was 3 days (interquartile range: 2-6 days). Three patients died during ICU admission. The median OS of the patients who were discharged from the ICU was 18 months (95% confidence interval, 5.0-NA). CONCLUSION: The incidence of irAEs leading to ICU admission in patients treated with ICI was low in this study. ICU mortality due to irAEs was low and a subset of this patient population even had long-term survival.
Subject(s)
Immune Checkpoint Inhibitors , Intensive Care Units , Neoplasms , Humans , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/therapeutic use , Male , Female , Intensive Care Units/statistics & numerical data , Retrospective Studies , Middle Aged , Aged , Neoplasms/drug therapy , Neoplasms/mortality , Adult , Incidence , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/mortality , Aged, 80 and over , CTLA-4 Antigen/antagonists & inhibitorsABSTRACT
INTRODUCTION: Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble autoimmune diseases, autoantibodies might play a role and could potentially be used to identify patients at risk. Therefore, we investigated the association between autoantibody-positivity and toxicity as well as clinical response in patients with melanoma treated with anti-PD-1. MATERIALS AND METHODS: This two-center, retrospective study included 143 patients with melanoma treated with anti-PD-1. Toxicities grade ≥2 and recurrences/responses were captured until 6 months after treatment initiation. Autoantibody measurements were performed at baseline and 3 months after treatment initiation, including IgM-rheumatoid factor (RF), antinuclear antibodies (ANA), extractable nuclear antigen, anti-cyclic citrullinated peptide antibodies (anti-CCP2) and anti-thyroid antibodies. RESULTS: 169 irAEs were experienced by 86/143 patients (137 grades 1-2, 32 grades 3-4), the most common being thyroiditis (n=25), dermatitis (n=24), and sicca problems (n=19). Patients with autoantibodies at baseline experienced more irAEs (p=0.001), predominantly associated with anti-thyroid antibodies and thyroid dysfunction. No association was observed between any irAE and anti-CCP2, RF or ANA. In women, baseline and on-treatment anti-thyroid antibody-positivity as well as seroconversion during treatment was associated with thyroid dysfunction. In men, this association was only observed on-treatment. The presence of autoantibodies was not associated with melanoma recurrence (p=0.776) or response (p=0.597). CONCLUSION: The presence of autoantibodies prior to anti-PD-1 therapy is associated with irAEs in patients with melanoma. Both baseline positivity and seroconversion of anti-thyroid antibodies were strongly associated with thyroid dysfunction. This association was stronger in women, with all women who were baseline positive developing thyroid dysfunction.
Subject(s)
Autoantibodies , Immune Checkpoint Inhibitors , Melanoma , Seroconversion , Humans , Melanoma/drug therapy , Melanoma/immunology , Female , Male , Autoantibodies/blood , Autoantibodies/immunology , Middle Aged , Retrospective Studies , Aged , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/therapeutic use , Adult , Aged, 80 and over , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunologyABSTRACT
BACKGROUND: Phase 1-2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy. METHODS: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival. RESULTS: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of the patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% among patients in the neoadjuvant group who had a major pathological response, 76.1% among those who had a partial response, and 57.0% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% in the adjuvant group. CONCLUSIONS: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.).
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PURPOSE: This prospective study evaluates the biodistribution of 18 F-FLT PET in patients with advanced melanoma before and after treatment with BRAF/MEK inhibitors. PATIENTS AND METHODS: Eighteen BRAF-positive unresectable stage IIIc or IV melanoma patients referred for 18 F-FLT PET/CT before (BL) and during (D14) BRAF/MEK inhibition were included. 18 F-FLT accumulation in the liver, bone marrow, blood, and muscle was quantified. RESULTS: Baseline interpatient 18 F-FLT uptake had a coefficient-of-variation between 17.5% and 21.5%. During treatment, liver uptake increased (SUV meanBL = 4.86 ± 0.98, SUV meanD14 = 6.31 ± 1.36, P < 0.001) and bone marrow uptake decreased (SUV meanBL = 7.67 ± 1.65, SUV meanD14 = 6.78 ± 1.19, P < 0.025). Both changes were unrelated to baseline metabolic tumor volume or tumor response. CONCLUSIONS: To assess 18 F-FLT PET, both liver and bone marrow uptake may be used as normal tissue references at baseline, but 18 F-FLT biodistribution significantly changes in longitudinal response studies when treated with BRAF/MEK inhibitors.
Subject(s)
Dideoxynucleosides , Melanoma , Positron Emission Tomography Computed Tomography , Humans , Melanoma/diagnostic imaging , Melanoma/drug therapy , Melanoma/metabolism , Tissue Distribution , Middle Aged , Male , Female , Dideoxynucleosides/pharmacokinetics , Aged , Adult , Neoplasm Staging , Biological TransportABSTRACT
We evaluated the prognostic value of hypoalbuminemia in context of various biomarkers at baseline, including clinical, genomic, transcriptomic, and blood-based markers, in patients with metastatic melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anti-CTLA-4 combination therapy (n = 178). An independent validation cohort (n = 79) was used to validate the performance of hypoalbuminemia compared to serum LDH (lactate dehydrogenase) levels. Pre-treatment hypoalbuminemia emerged as the strongest predictor of poor outcome for both OS (HR = 4.01, 95% CI 2.10-7.67, Cox P = 2.63e-05) and PFS (HR = 3.72, 95% CI 2.06-6.73, Cox P = 1.38e-05) in univariate analysis. In multivariate analysis, the association of hypoalbuminemia with PFS was independent of serum LDH, IFN-γ signature expression, TMB, age, ECOG PS, treatment line, treatment type (combination or monotherapy), brain and liver metastasis (HR = 2.76, 95% CI 1.24-6.13, Cox P = 0.0131). Our validation cohort confirmed the prognostic power of hypoalbuminemia for OS (HR = 1.98, 95% CI 1.16-3.38; Cox P = 0.0127) and was complementary to serum LDH in analyses for both OS (LDH-adjusted HR = 2.12, 95% CI 1.2-3.72, Cox P = 0.00925) and PFS (LDH-adjusted HR = 1.91, 95% CI 1.08-3.38, Cox P = 0.0261). In conclusion, pretreatment hypoalbuminemia was a powerful predictor of outcome in ICI in melanoma and showed remarkable complementarity to previously established biomarkers, including high LDH.
Subject(s)
Biomarkers, Tumor , Hypoalbuminemia , Immune Checkpoint Inhibitors , Melanoma , Humans , Melanoma/drug therapy , Melanoma/pathology , Melanoma/metabolism , Female , Male , Middle Aged , Biomarkers, Tumor/blood , Aged , Immune Checkpoint Inhibitors/therapeutic use , Prognosis , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/metabolism , Adult , Neoplasm Metastasis , L-Lactate Dehydrogenase/blood , L-Lactate Dehydrogenase/metabolism , Aged, 80 and over , MultiomicsABSTRACT
PURPOSE: The development of resistance limits the clinical benefit of BRAF and MEK inhibitors (BRAFi/MEKi) in BRAFV600-mutated melanoma. It has been shown that short-term treatment (14 days) with vorinostat was able to initiate apoptosis of resistant tumor cells. We aimed to assess the antitumor activity of sequential treatment with vorinostat following BRAFi/MEKi in patients with BRAFV600-mutated melanoma who progressed after initial response to BRAFi/MEKi. PATIENTS AND METHODS: Patients with BRAFi/MEKi-resistant BRAFV600-mutated melanoma were treated with vorinostat 360 mg once daily for 14 days followed by BRAFi/MEKi. The primary endpoint was an objective response rate of progressive lesions of at least 30% according to Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included progression-free survival, overall survival, safety, pharmacokinetics of vorinostat, and translational molecular analyses using ctDNA and tumor biopsies. RESULTS: Of the 26 patients with progressive BRAFi/MEKi-resistant BRAFV600-mutated melanoma receiving treatment with vorinostat, 22 patients were evaluable for response. The objective response rate was 9%, with one complete response for 31.2 months and one partial response for 14.9 months. Median progression-free survival and overall survival were 1.4 and 5.4 months, respectively. Common adverse events were fatigue (23%) and nausea (19%). ctDNA analysis showed emerging secondary mutations in NRAS and MEK in eight patients at the time of BRAFi/MEKi resistance. Elimination of these mutations by vorinostat treatment was observed in three patients. CONCLUSIONS: Intermittent treatment with vorinostat in patients with BRAFi/MEKi-resistant BRAFV600-mutated melanoma is well tolerated. Although the primary endpoint of this study was not met, durable antitumor responses were observed in a minority of patients (9%).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Histone Deacetylase Inhibitors , Melanoma , Mutation , Protein Kinase Inhibitors , Proto-Oncogene Proteins B-raf , Vorinostat , Humans , Melanoma/drug therapy , Melanoma/genetics , Melanoma/pathology , Melanoma/mortality , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Vorinostat/administration & dosage , Vorinostat/pharmacology , Female , Male , Middle Aged , Aged , Adult , Histone Deacetylase Inhibitors/administration & dosage , Histone Deacetylase Inhibitors/therapeutic use , Histone Deacetylase Inhibitors/adverse effects , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Proof of Concept Study , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/drug effects , Aged, 80 and overABSTRACT
Therapeutic approaches for clear cell renal cell carcinoma (ccRCC) remain limited; however, chimeric antigen receptor (CAR) T-cell therapies may offer novel treatment options. CTX130, an allogeneic CD70-targeting CAR T-cell product, was developed for the treatment of advanced or refractory ccRCC. We report that CTX130 showed favorable preclinical proliferation and cytotoxicity profiles and completely regressed RCC xenograft tumors. We also report results from 16 patients with relapsed/refractory ccRCC who received CTX130 in a phase I, multicenter, first-in-human clinical trial. No patients encountered dose-limiting toxicity, and disease control was achieved in 81.3% of patients. One patient remains in a durable complete response at 3 years. Finally, we report on a next-generation CAR T construct, CTX131, in which synergistic potency edits to CTX130 confer improved expansion and efficacy in preclinical studies. These data represent a proof of concept for the treatment of ccRCC and other CD70+ malignancies with CD70- targeted allogeneic CAR T cells. Significance: Although the role of CAR T cells is well established in hematologic malignancies, the clinical experience in solid tumors has been disappointing. This clinical trial demonstrates the first complete response in a patient with RCC, reinforcing the potential benefit of CAR T cells in the treatment of solid tumors.
Subject(s)
CD27 Ligand , Carcinoma, Renal Cell , Immunotherapy, Adoptive , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/therapy , Carcinoma, Renal Cell/immunology , Animals , Kidney Neoplasms/therapy , Kidney Neoplasms/immunology , Immunotherapy, Adoptive/methods , Mice , Female , Male , Middle Aged , Receptors, Chimeric Antigen/immunology , Aged , Xenograft Model Antitumor Assays , Cell Line, Tumor , AdultABSTRACT
INTRODUCTION: Naked DNA vaccination could be a powerful and safe strategy to mount antigen-specific cellular immunity. We designed a phase I clinical trial to investigate the toxicity of naked DNA vaccines encoding CD8+ T-cell epitope from tumor-associated antigen MART-1 in patients with advanced melanoma. METHODS: This dose escalating phase Ia clinical trial investigates the toxicity and immunological response upon naked DNA vaccines encoding a CD8+ T-cell epitope from the tumor-associated antigen MART-1, genetically linked to the gene encoding domain 1 of subunit-tetanus toxin fragment C in patients with advanced melanoma (inoperable stage IIIC-IV, AJCC 7th edition). The vaccine was administrated via intradermal application using a permanent make-up or tattoo device. Safety was monitored according to CTCAE v.3.0 and skin biopsies and blood samples were obtained for immunologic monitoring. RESULTS: Nine pretreated, HLA-A*0201-positive patients with advanced melanoma expressing MART-1 and MHC class I, with a good performance status, and adequate organ function, were included. With a median follow-up of 5.9 months, DNA vaccination was safe, without treatment-related deaths. Common treatment-emergent adverse events of any grade were dermatologic reactions at the vaccination site (100%) and pain (56%). One patient experienced grade 4 toxicity, most likely related to tumor progression. One patient (11%) achieved stable disease, lasting 353 days. Immune analysis showed no increase in vaccine-induced T cell response in peripheral blood of 5 patients, but did show a MART-1 specific CD8+ T cell response at the tattoo administration site. The maximum dose administered was 2 mg due to lack of clinical activity. CONCLUSION: We showed that the developed DNA vaccine, applied using a novel intradermal application strategy, can be administered safely. Further research with improved vaccine formats is required to show possible clinical benefit of DNA vaccination.
Subject(s)
Cancer Vaccines , Melanoma , Neoplasm Staging , Tattooing , Vaccines, DNA , Humans , Melanoma/immunology , Melanoma/therapy , Vaccines, DNA/administration & dosage , Vaccines, DNA/immunology , Middle Aged , Female , Male , Cancer Vaccines/administration & dosage , Cancer Vaccines/immunology , Cancer Vaccines/therapeutic use , Injections, Intradermal , Aged , Adult , Skin Neoplasms/immunology , MART-1 Antigen/immunology , CD8-Positive T-Lymphocytes/immunology , Vaccination/methods , Treatment Outcome , HLA-A2 Antigen/immunology , Epitopes, T-Lymphocyte/immunologyABSTRACT
T cell receptor (TCR) gene therapy is a potent form of cellular immunotherapy in which patient T cells are genetically engineered to express TCRs with defined tumor reactivity. However, the isolation of therapeutic TCRs is complicated by both the general scarcity of tumor-specific T cells among patient T cell repertoires and the patient-specific nature of T cell epitopes expressed on tumors. Here we describe a high-throughput, personalized TCR discovery pipeline that enables the assembly of complex synthetic TCR libraries in a one-pot reaction, followed by pooled expression in reporter T cells and functional genetic screening against patient-derived tumor or antigen-presenting cells. We applied the method to screen thousands of tumor-infiltrating lymphocyte (TIL)-derived TCRs from multiple patients and identified dozens of CD4+ and CD8+ T-cell-derived TCRs with potent tumor reactivity, including TCRs that recognized patient-specific neoantigens.
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Background: The DRUG Access Protocol provides patients with cancer access to registered anti-cancer drugs that are awaiting reimbursement in the Netherlands and simultaneously collects prospective real-world data (RWD). Here, we present RWD from PD-1 blocker cemiplimab in patients with locally advanced or metastatic cutaneous squamous cell carcinoma (laCSCC; mCSCC). Methods: Patients with laCSCC or mCSCC received cemiplimab 350 mg fixed dose every three weeks. Primary endpoints were objective clinical benefit rate (CBR), defined as objective response (OR) or stable disease (SD) at 16 weeks, physician-assessed CBR, defined as clinician's documentation of improved disease or SD based on evaluation of all available clinical parameters at 16 weeks, objective response rate (ORR), and safety, defined as grade ≥ 3 treatment related adverse events (TRAEs) occurring up to 30 days after last drug administration. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Findings: Between February 2021 and December 2022, 151 patients started treatment. Objective and physician-assessed CBR were 54.3% (95% CI, 46.0-62.4) and 59.6% (95% CI, 51.3-67.5), respectively. ORR was 35.1% (95% CI, 27.5-43.3). After a median follow-up of 15.2 months, median DoR was not reached. Median PFS and OS were 12.2 (95% CI, 7.0-not reached) and 24.2 months (95% CI, 18.8-not reached), respectively. Sixty-eight TRAEs occurred in 29.8% of patients. Most commonly reported TRAE was a kidney transplant rejection (9.5%). Interpretation: Cemiplimab proved highly effective and safe in this real-world cohort of patients with laCSCC or mCSCC, confirming its therapeutic value in the treatment of advanced CSCC in daily clinical practice. Funding: The DRUG Access Protocol is supported by all participating pharmaceutical companies: Bayer, Janssen, Lilly, Merck, Novartis, Roche, and Sanofi.
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ABSTRACT: Major progress in prolonging survival of patients with advanced melanoma has been made in the past decade because of the development and approval of immune checkpoint inhibitor and targeted therapies. However, for nonresponding or relapsing patients, their prognosis is still dismal. Based on clinical trial data, treatment with adoptive cell therapies holds great promise. In patients with metastatic melanoma progressing on or nonresponsive to single-agent anti-programmed cell death 1, infusion of tumor-infiltrating lymphocytes can produce responses in up to half of patients, with durable complete responses in up to 20%. Genetic modification of peripheral blood T cells with T-cell receptors derived from tumor-specific T cells, or with chimeric antigen receptors, has the potential to further improve treatment outcomes in this refractory population. In this review, we will discuss the historical development, current status, and future perspectives of adoptive T-cell therapies in melanoma.
Subject(s)
Lymphocytes, Tumor-Infiltrating , Melanoma , Humans , Neoplasm Recurrence, Local , Immunotherapy, Adoptive , ImmunotherapyABSTRACT
The phase III JAVELIN Renal 101 trial demonstrated prolonged progression-free survival (PFS) in patients (N = 886) with advanced renal cell carcinoma treated with first-line avelumab + axitinib (A+Ax) versus sunitinib. We report novel findings from integrated analyses of longitudinal blood samples and baseline tumor tissue. PFS was associated with elevated lymphocyte levels in the sunitinib arm and an abundance of innate immune subsets in the A+Ax arm. Treatment with A+Ax led to greater T-cell repertoire modulation and less change in T-cell numbers versus sunitinib. In the A+Ax arm, patients with tumors harboring mutations in ≥2 of 10 previously identified PFS-associated genes (double mutants) had distinct circulating and tumor-infiltrating immunologic profiles versus those with wild-type or single-mutant tumors, suggesting a role for non-T-cell-mediated and non-natural killer cell-mediated mechanisms in double-mutant tumors. We provide evidence for different immunomodulatory mechanisms based on treatment (A+Ax vs. sunitinib) and tumor molecular subtypes. SIGNIFICANCE: Our findings provide novel insights into the different immunomodulatory mechanisms governing responses in patients treated with avelumab (PD-L1 inhibitor) + axitinib or sunitinib (both VEGF inhibitors), highlighting the contribution of tumor biology to the complexity of the roles and interactions of infiltrating immune cells in response to these treatment regimens. This article is featured in Selected Articles from This Issue, p. 384.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/genetics , Sunitinib/therapeutic use , Axitinib , Biomarkers , Kidney Neoplasms/drug therapy , Kidney Neoplasms/geneticsABSTRACT
Autologous natural dendritic cells (nDCs) treatment can induce tumor-specific immune responses and clinical responses in cancer patients. In this phase III clinical trial (NCT02993315), 148 patients with resected stage IIIB/C melanoma were randomized to adjuvant treatment with nDCs (n = 99) or placebo (n = 49). Active treatment consisted of intranodally injected autologous CD1c+ conventional and plasmacytoid DCs loaded with tumor antigens. The primary endpoint was the 2-year recurrence-free survival (RFS) rate, whereas the secondary endpoints included median RFS, 2-year and median overall survival, adverse event profile, and immunological response The 2-year RFS rate was 36.8% in the nDC treatment group and 46.9% in the control group (p = 0.31). Median RFS was 12.7 months vs 19.9 months, respectively (hazard ratio 1.25; 90% CI: 0.88-1.79; p = 0.29). Median overall survival was not reached in both treatment groups (hazard ratio 1.32; 90% CI: 0.73-2.38; p = 0.44). Grade 3-4 study-related adverse events occurred in 5% and 6% of patients. Functional antigen-specific T cell responses could be detected in 67.1% of patients tested in the nDC treatment group vs 3.8% of patients tested in the control group (p < 0.001). In conclusion, while adjuvant nDC treatment in stage IIIB/C melanoma patients generated specific immune responses and was well tolerated, no benefit in RFS was observed.
Subject(s)
Melanoma , Skin Neoplasms , Humans , Skin Neoplasms/pathology , Disease-Free Survival , Adjuvants, Immunologic/therapeutic use , Dendritic Cells/pathology , Neoplasm StagingABSTRACT
Immunotherapy with immune-checkpoint inhibitors (ICIs) and targeted therapy with BRAF and MEK inhibitors have revolutionized the treatment of melanoma over the past decade. Despite these breakthroughs, the 5-year survival rate of patients with advanced-stage melanoma is at most 50%, emphasizing the need for additional therapeutic strategies. Adoptive cell therapy with tumour-infiltrating lymphocytes (TILs) is a therapeutic modality that has, in the past few years, demonstrated long-term clinical benefit in phase II/III trials involving patients with advanced-stage melanoma, including those with disease progression on ICIs and/or BRAF/MEK inhibitors. In this Review, we summarize the current status of TIL therapies for patients with advanced-stage melanoma, including potential upcoming marketing authorization, the characteristics of TIL therapy products, as well as future strategies that are expected to increase the efficacy of this promising cellular immunotherapy.
Subject(s)
Melanoma , Humans , Melanoma/therapy , Immunotherapy, Adoptive , Lymphocytes, Tumor-Infiltrating , Proto-Oncogene Proteins B-raf , Mitogen-Activated Protein Kinase KinasesABSTRACT
Gastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements, most patients die of their disease. Although immune checkpoint blockade became part of the standard-of-care for patients with metastatic G/GEJ cancers, its efficacy and impact on the tumor microenvironment (TME) in early disease remain largely unknown. We hypothesized higher efficacy of neoadjuvant immunotherapy plus chemotherapy in patients with nonmetastatic G/GEJ cancer. In the phase 2 PANDA trial, patients with previously untreated resectable G/GEJ tumors (n = 21) received neoadjuvant treatment with one cycle of atezolizumab monotherapy followed by four cycles of atezolizumab plus docetaxel, oxaliplatin and capecitabine. Treatment was well tolerated. There were grade 3 immune-related adverse events in two of 20 patients (10%) but no grade 4 or 5 immune-related adverse events, and all patients underwent resection without treatment-related delays, meeting the primary endpoint of safety and feasibility. Tissue was obtained at multiple time points, allowing analysis of the effects of single-agent anti-programmed cell death ligand 1 (PD-L1) and the subsequent combination with chemotherapy on the TME. Twenty of 21 patients underwent surgery and were evaluable for secondary pathologic response and survival endpoints, and 19 were evaluable for exploratory translational analyses. A major pathologic response (≤10% residual viable tumor) was observed in 14 of 20 (70%, 95% confidence interval 46-88%) patients, including 9 (45%, 95% confidence interval 23-68%) pathologic complete responses. At a median follow-up of 47 months, 13 of 14 responders were alive and disease-free, and five of six nonresponders had died as a result of recurrence. Notably, baseline anti-programmed cell death protein 1 (PD-1)+CD8+ T cell infiltration was significantly higher in responders versus nonresponders, and comparison of TME alterations following anti-PD-L1 monotherapy versus the subsequent combination with chemotherapy showed an increased immune activation on single-agent PD-1/L1 axis blockade. On the basis of these data, monotherapy anti-PD-L1 before its combination with chemotherapy warrants further exploration and validation in a larger cohort of patients with nonmetastatic G/GEJ cancer. ClinicalTrials.gov registration: NCT03448835 .
Subject(s)
Adenocarcinoma , Antibodies, Monoclonal, Humanized , Esophageal Neoplasms , Stomach Neoplasms , Humans , Neoadjuvant Therapy , Programmed Cell Death 1 Receptor , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Esophagogastric Junction/pathology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Tumor MicroenvironmentABSTRACT
Predicting who will benefit from treatment with immune checkpoint inhibition (ICI) in patients with advanced melanoma is challenging. We developed a multivariable prediction model for response to ICI, using routinely available clinical data including primary melanoma characteristics. We used a population-based cohort of 3525 patients with advanced cutaneous melanoma treated with anti-PD-1-based therapy. Our prediction model for predicting response within 6 months after ICI initiation was internally validated with bootstrap resampling. Performance evaluation included calibration, discrimination and internal-external cross-validation. Included patients received anti-PD-1 monotherapy (n = 2366) or ipilimumab plus nivolumab (n = 1159) in any treatment line. The model included serum lactate dehydrogenase, World Health Organization performance score, type and line of ICI, disease stage and time to first distant recurrence-all at start of ICI-, and location and type of primary melanoma, the presence of satellites and/or in-transit metastases at primary diagnosis and sex. The over-optimism adjusted area under the receiver operating characteristic was 0.66 (95% CI: 0.64-0.66). The range of predicted response probabilities was 7%-81%. Based on these probabilities, patients were categorized into quartiles. Compared to the lowest response quartile, patients in the highest quartile had a significantly longer median progression-free survival (20.0 vs 2.8 months; P < .001) and median overall survival (62.0 vs 8.0 months; P < .001). Our prediction model, based on routinely available clinical variables and primary melanoma characteristics, predicts response to ICI in patients with advanced melanoma and discriminates well between treated patients with a very good and very poor prognosis.
Subject(s)
Melanoma , Skin Neoplasms , Humans , Melanoma/pathology , Immune Checkpoint Inhibitors/therapeutic use , Skin Neoplasms/pathology , Ipilimumab/therapeutic use , Nivolumab/therapeutic use , Retrospective StudiesABSTRACT
PURPOSE: The aims of this study were to investigate whether (early) PERCIST response monitoring with 18 F-FDG PET/CT is predictive for progression-free survival (PFS) in unresectable stage III or IV melanoma patients treated with BRAF/MEK inhibitor (MEKi) and to define dissemination patterns at progression with a lesion-based evaluation in direct comparison to baseline to improve our understanding of 18 F-FDG PET/CT during BRAF/MEKi. PATIENTS AND METHODS: This prospective multicenter single-arm study included 70 patients with unresectable stage III/IV BRAF -mutated melanoma who underwent contrast-enhanced CT and 18 F-FDG PET/CT at baseline and 2 and 7 weeks during treatment with vemurafenib plus cobimetinib and at progression if possible. Tumor response assessment was done with RECIST1.1 and PERCIST. Follow-up PET/CT scans were visually compared with baseline to assess dissemination patterns. RESULTS: Using RECIST1.1, PFS was not significantly different between the response groups ( P = 0.26). At 2 weeks, PERCIST median PFS was 15.7 months for patients with complete metabolic response (CMR) versus 8.3 months for non-CMR ( P = 0.035). The hazards ratio (HR) for progression/death in non-CMR versus CMR was 1.99 (95% confidence interval [CI], 1.03-3.84; P = 0.040) and 1.77 (95% CI, 0.91-3.43; P = 0.0935) when adjusting for lactate dehydrogenase (LDH). At 7 weeks, median PFS for PERCIST CMR was 16.7 months versus 8.5 months for non-CMR ( P = 0.0003). The HR for progression/death in the non-CMR group was significantly increased (HR, 2.94; 95% CI, 1.60-5.40; P = 0.0005), even when adjusting for LDH (HR, 2.65; 95% CI, 1.43-4.91; P = 0.0020). At week 7, 18 F-FDG PET/CT was false-positive in all 4 (6%) patients with new FDG-avid lesions but CMR of known metastases. When 18 F-FDG PET/CT was performed at progressive disease, 18/22 (82%) patients had progression of known metastases with or without new 18 F-FDG-avid lesions. CONCLUSIONS: This study shows that PERCIST response assessment at week 7 is predictive for PFS, regardless of LDH. At 2 weeks, patients with CMR have longer PFS than patients with non-CMR, but different PET parameters should be investigated to further evaluate the added value of early 18 F-FDG PET/CT. Disease progression on PET/CT is predominated by progression of known metastases, and new 18 F-FDG-avid lesions during BRAF/MEKi are not automatically a sign of recurrent disease.
Subject(s)
Melanoma , Skin Neoplasms , Humans , Melanoma/diagnostic imaging , Melanoma/drug therapy , Melanoma/genetics , Positron Emission Tomography Computed Tomography , Fluorodeoxyglucose F18 , Proto-Oncogene Proteins B-raf/genetics , Progression-Free Survival , Prospective Studies , Skin Neoplasms/pathology , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic useABSTRACT
Immune checkpoint blockade has become standard treatment for many types of cancer. Such therapy is indicated most often in patients with advanced or metastatic disease but has been increasingly used as adjuvant therapy in those with early-stage disease. Adverse events include immune-related organ inflammation resembling autoimmune diseases. We describe a case of severe immune-related gastroenterocolitis in a 4-month-old infant who presented with intractable diarrhea and failure to thrive after in utero exposure to pembrolizumab. Known causes of the symptoms were ruled out, and the diagnosis of pembrolizumab-induced immune-related gastroenterocolitis was supported by the results of histopathological assays, immunophenotyping, and analysis of the level of antibodies against programmed cell death protein 1 (PD-1). The infant's condition was successfully treated with prednisolone and infliximab.