Adoptive Cell Therapy for Solid Tumors: Current Status in Melanoma and Next-Generation Therapies.

Lifileucel or TIL has recently been FDA approved for metastatic melanoma patients as first cell therapy for a solid tumor. We discuss roll-out of TIL as new SOC and other upcoming new cell therapies.

Multi-omic analysis identifies hypoalbuminemia as independent biomarker of poor outcome upon PD-1 blockade in metastatic melanoma.

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.

A proof-of-concept study of sequential treatment with the HDAC inhibitor vorinostat following BRAF and MEK inhibitors in BRAFV600mutated melanoma.

PURPOSE: 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 the resistant tumor cells. We aimed to assess the anti-tumor activity of sequential treatment with vorinostat following BRAFi/MEKi in patients with BRAFV600 melanoma who progressed after initial response to BRAFi/MEKi. PATIENTS AND METHODS: Patients with BRAFi/MEKi resistant BRAFV600 melanoma were treated with vorinostat 360 mg QD for 14 days followed by BRAFi/MEKi. The primary endpoint was an objective response rate of progressive lesions of at least 30% according to RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, pharmacokinetics of vorinostat and translational molecular analyses using ctDNA and tumor biopsies. RESULTS: Twenty-six patients with progressive BRAFi/MEKi resistant BRAFV600 mutated melanoma received treatment with vorinostat. Twenty-two patients were evaluable for response. The ORR was 9% (one complete response for 31.2 months and one partial response for 14.9 months. Median PFS and OS 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 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 resistant BRAFV600mutated melanoma is well tolerated. Although the primary endpoint of this study was not met, durable anti-tumor responses were observed in a minority of patients (9%).

Baseline and on Treatment Biodistribution Variability of 18F-FLT Uptake in Patients With Advanced Melanoma: Brief Communication.

PURPOSE: This prospective study evaluates the biodistribution of 18F-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 18F-FLT PET/CT before (BL) and during (D14) BRAF/MEK inhibition were included. 18F-FLT accumulation in the liver, bone marrow, blood, and muscle was quantified. RESULTS: Baseline interpatient 18F-FLT uptake had a coefficient-of-variation between 17.5% and 21.5%. During treatment, liver uptake increased (SUVmeanBL = 4.86 ± 0.98, SUVmeanD14 = 6.31 ± 1.36, P < 0.001) and bone marrow uptake decreased (SUVmeanBL = 7.67 ± 1.65, SUVmeanD14 = 6.78 ± 1.19, P < 0.025). Both changes were unrelated to baseline metabolic tumor volume or tumor response. CONCLUSIONS: To assess 18F-FLT PET, both liver and bone marrow uptake may be used as normal tissue references at baseline, but 18F-FLT biodistribution significantly changes in longitudinal response studies when treated with BRAF/MEK inhibitors.

Melanoma neoantigen vaccines: Are we getting more personal now?

KEYNOTE-9421 is a randomized phase II adjuvant study in patients with resected stage III melanoma investigating a personalized neoantigen mRNA vaccine in combination with anti-PD-1. The study gave a clear signal of superiority for the vaccine plus anti-PD-1 in relapse-free and distant-metastasis-free survival but is not yet conclusive, and important questions remain.

Discovery of tumor-reactive T cell receptors by massively parallel library synthesis and screening.

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.

CD70-Targeted Allogeneic CAR T-Cell Therapy for Advanced Clear Cell Renal Cell Carcinoma.

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.

Intradermal naked DNA vaccination by DNA tattooing for mounting tumor-specific immunity in stage IV melanoma patients: a phase I clinical trial.

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 five 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.

Cemiplimab in locally advanced or metastatic cutaneous squamous cell carcinoma: prospective real-world data from the DRUG Access Protocol.

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.

Tumor-Infiltrating Lymphocyte and Other Cell Therapies for Metastatic Melanoma.

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.

Cost-effectiveness of treating advanced melanoma with tumor-infiltrating lymphocytes based on an international randomized phase 3 clinical trial.

INTRODUCTION: In a multicenter, open-label randomized phase 3 clinical trial conducted in the Netherlands and Denmark, treatment with ex vivo-expanded tumor-infiltrating lymphocytes (TIL-NKI/CCIT) from autologous melanoma tumor compared with ipilimumab improved progression-free survival in patients with unresectable stage IIIC-IV melanoma after failure of first-line or second-line treatment. Based on this trial, we conducted a cost-utility analysis. METHODS: A Markov decision model was constructed to estimate expected costs (expressed in 2021€) and outcomes (quality-adjusted life years (QALYs)) of TIL-NKI/CCIT versus ipilimumab in the Netherlands. The Danish setting was assessed in a scenario analysis. A modified societal perspective was applied over a lifetime horizon. TIL-NKI/CCIT production costs were estimated via activity-based costing. Through sensitivity analyses, uncertainties and their impact on the incremental cost-effectiveness ratio (ICER) were assessed. RESULTS: Mean total undiscounted lifetime benefits were 4.47 life years (LYs) and 3.52 QALYs for TIL-NKI/CCIT and 3.33 LYs and 2.46 QALYs for ipilimumab. Total lifetime undiscounted costs in the Netherlands were €347,168 for TIL-NKI/CCIT (including €67,547 for production costs) compared with €433,634 for ipilimumab. Undiscounted lifetime cost in the Danish scenario were €337,309 and €436,135, respectively. This resulted in a dominant situation for TIL-NKI/CCIT compared with ipilimumab in both countries, meaning incremental QALYs were gained at lower costs. Survival probabilities, and utility in progressive disease affected the ICER most. CONCLUSION: Based on the data of a randomized phase 3 trial, treatment with TIL-NKI/CCIT in patients with unresectable stage IIIC-IV melanoma is cost-effective and cost-saving, both in the current Dutch and Danish setting. These findings led to inclusion of TIL-NKI/CCIT as insured care and treatment guidelines. Publicly funded development of the TIL-NKI/CCIT cell therapy shows realistic promise to further explore development of effective personalized treatment while warranting economic sustainability of healthcare systems.

Adjuvant dendritic cell therapy in stage IIIB/C melanoma: the MIND-DC randomized phase III trial.

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.

Integrative Analyses of Tumor and Peripheral Biomarkers in the Treatment of Advanced Renal Cell Carcinoma.

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.

Improving survival in advanced melanoma patients: a trend analysis from 2013 to 2021.

Background: The prognosis of advanced melanoma patients has significantly improved over the years. We aimed to evaluate the survival per year of diagnosis. Methods: All systemically treated patients diagnosed with advanced melanoma from 2013 to 2021 were included from the Dutch Melanoma Treatment Registry. Baseline characteristics and overall survival (OS) were compared between the different years of diagnosis. A multivariable Cox proportional hazards model was used to estimate the association between year of diagnosis and OS. Findings: For this cohort study, we included 6260 systemically treated advanced melanoma patients. At baseline, there was an increase over the years in age, the percentage of patients with an ECOG PS ≥ 2, with brain metastases, and a synchronous diagnosis of primary and unresectable melanoma. Median OS increased from 11.2 months (95% CI 10.0-12.4) for patients diagnosed in 2013 to 32.0 months (95% CI 26.6-36.7) for patients diagnosed in 2019. Median OS was remarkably lower for patients diagnosed in 2020 (26.6 months; 95% CI 23.9-35.1) and 2021 (24.0 months; 95% CI 20.4-NR). Patients diagnosed in 2020 and 2021 had a higher hazard of death compared to patients diagnosed in 2019, although this was not significant. The multivariable Cox regression showed a lower hazard of death for the years of diagnosis after 2013. In contrast, patients diagnosed in 2020 and 2021 had a higher hazard of death compared to patients diagnosed in 2019. Interpretation: After a continuous survival improvement for advanced melanoma patients between 2013 and 2019, outcomes of patients diagnosed in 2020 and 2021 seem poorer. This trend of decreased survival remained after correcting for known prognostic factors and previous neoadjuvant or adjuvant treatment, suggesting that it is explained by unmeasured factors, which-considering the timing-could be COVID-19-related. Funding: For the Dutch Melanoma Treatment Registry (DMTR), the Dutch Institute for Clinical Auditing foundation received a start-up grant from governmental organization The Netherlands Organization for Health Research and Development (ZonMW, project number 836002002). The DMTR is structurally funded by Bristol-Myers Squibb, Merck Sharpe & Dohme, Novartis, and Roche Pharma. Roche Pharma stopped funding in 2019, and Pierre Fabre started funding the DMTR in 2019. For this work, no funding was granted.

Expert consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy.

Adoptive cell therapy with autologous, ex vivo-expanded, tumor-infiltrating lymphocytes (TILs) is being investigated for treatment of solid tumors and has shown robust responses in clinical trials. Based on the encouraging efficacy, tolerable safety profile, and advancements in a central manufacturing process, lifileucel is now the first US Food and Drug Administration (FDA)-approved TIL cell therapy product. To this end, treatment management and delivery practice guidance is needed to ensure successful integration of this modality into clinical care. This review includes clinical and toxicity management guidelines pertaining to the TIL cell therapy regimen prepared by the TIL Working Group, composed of internationally recognized hematologists and oncologists with expertize in TIL cell therapy, and relates to patient care and operational aspects. Expert consensus recommendations for patient management, including patient eligibility, screening tests, and clinical and toxicity management with TIL cell therapy, including tumor tissue procurement surgery, non-myeloablative lymphodepletion, TIL infusion, and IL-2 administration, are discussed in the context of potential standard of care TIL use. These recommendations provide practical guidelines for optimal clinical management during administration of the TIL cell therapy regimen, and recognition of subsequent management of toxicities. These guidelines are focused on multidisciplinary teams of physicians, nurses, and stakeholders involved in the care of these patients.

Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial.

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 .

No detrimental association between antibiotic use and immune checkpoint inhibitor therapy: an observational cohort study comparing patients with ICI-treated and TKI-treated melanoma and NSCLC.

BACKGROUND: The role of antibiotics in malignancies treated with immune checkpoint inhibitors (ICI) remains unclear. Several studies suggested a detrimental impact of antibiotic use on the response to ICI, but were susceptible to confounding by indication. Our objective was therefore to assess whether the relationship between antibiotic use and ICI response is causative or merely associative. METHODS: A large, single-center observational cohort study was performed with individuals treated for either non-small cell lung carcinoma (NSCLC) or metastatic melanoma. An effect modification approach was used, aiming to estimate the association between antibiotic use and overall survival (OS) and compare these estimates between individuals receiving first-line ICI treatment versus those receiving first-line tyrosine kinase inhibitors (TKIs). Exposure of interest was antibiotic use within 30 days before the start of anticancer treatment. HRs for OS were estimated for antibiotics versus no antibiotics in each cohort using multivariable propensity adjusted analysis. The "true antibiotic effect" within the ICI versus TKI cohort was modeled using an interaction term. RESULTS: A total of 4534 patients were included, of which 1908 in the ICI cohort and 817 in the TKI cohort. Approximately 10% of patients in each cohort used antibiotics within 30 days before the start of anticancer treatment. Our results demonstrate a lack of synergistic interaction between current antibiotic use and ICI therapy in relation to OS: although antibiotic use was significantly associated with OS decline in the ICI cohort (HR=1.26 (95% CI 1.04 to 1.51)), a similar magnitude in OS decline was found within the TKI cohort (HR=1.24 (95% CI 0.95 to 1.62)). This was reflected by the synergy index (HR=0.96 (95% CI 0.70 to 1.31)), which implied no synergistic interaction between current antibiotic use and ICI. CONCLUSION: This study strongly suggests that there is no causal detrimental association between antibiotic use and ICI therapy outcome when looking at OS in individuals with malignant melanoma or NSCLC. The frequently observed inverse association between antibiotics and ICI response in previous studies is most likely driven by confounding by indication, which was confirmed by the findings in our reference TKI cohort.

A prediction model for response to immune checkpoint inhibition in advanced melanoma.

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.

Tumour-infiltrating lymphocyte therapy for patients with advanced-stage melanoma.

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.