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Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

ABSTRACT: Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1.We enrolled patients with advanced melanoma, non-small-cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred.A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non-small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non-small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1-PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1-negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1-positive tumors had an objective response (P=0.006).Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.).

SUBMITTER: Topalian SL

PROVIDER: S-EPMC3544539 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

Topalian Suzanne L SL Hodi F Stephen FS Brahmer Julie R JR Gettinger Scott N SN Smith David C DC McDermott David F DF Powderly John D JD Carvajal Richard D RD Sosman Jeffrey A JA Atkins Michael B MB Leming Philip D PD Spigel David R DR Antonia Scott J SJ Horn Leora L Drake Charles G CG Pardoll Drew M DM Chen Lieping L Sharfman William H WH Anders Robert A RA Taube Janis M JM McMiller Tracee L TL Xu Haiying H Korman Alan J AJ Jure-Kunkel Maria M Agrawal Shruti S McDonald Daniel D Kollia Georgia D GD Gupta Ashok A Wigginton Jon M JM Sznol Mario M

The New England journal of medicine 20120602 26

<h4>Background</h4>Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1.<h4>Methods</h4>We enrolled patients with advanced melanoma, non-small-cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. ...[more]

PMID: 22658127

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Project description:BACKGROUND:JS001, a humanized IgG4 monoclonal antibody against the programmed death-1 (PD-1) receptor, blocks the interaction of PD-1 with its ligands and promotes T cell activation in preclinical studies. This phase I study is designed to evaluate the safety, tolerability, and clinical activity of JS001 in advanced melanoma or urologic cancer patients who are refractory to standard systemic therapy. PATIENTS AND METHODS:In the dose escalation cohorts, subjects initially received a single-dose, intravenous infusion of JS001, and were followed for 28?days followed by multi-dose infusions every 2 weeks. In the dose expansion cohorts, subjects received multi-dose infusions every 2 weeks. Clinical response was evaluated after each 8-week treatment cycle according to RECIST v1.1 criteria. RESULTS:Thirty-six subjects diagnosed with advanced melanoma (n?=?22), urothelial cancer (UC) (n?=?8), or renal cell cancer (RCC) (n?=?6) were enrolled. Melanoma subjects included 14 acral and 4 mucosal subtypes. JS001 was well tolerated, and no dose-limiting toxicity was observed. By the safety data cutoff date, 100% of subjects had treatment-related adverse events (TRAE) with most adverse events being grade 1 or 2, and ? grade 3 TRAEs occurred in 36%. Among all 36 subjects, 1 confirmed complete response (acral melanoma), 7 confirmed partial responses (2 acral melanoma, 1 mucosal melanoma, 2 UC, and 2 RCC), and 10 stable disease were observed, for an objective response rate of 22.2% (95% CI, 10.1 to 39.2), and a disease control rate of 50.0% (95% CI, 32.9 to 67.1). Clinical responses were correlated with PD-L1 expression on tumor cells, the presence of tumor infiltrating lymphocytes (TIL), baseline tumor volume, ECOG performance status, serum LDH levels, high percentage of activated CD8+ T cells and CD3- CD16+ CD54+ NK cells in the peripheral blood as well as tumor mutational burden (TMB). CONCLUSION:JS001 was well tolerated and demonstrated promising anti-tumor activity in UC and RCC as well as in previously underexplored acral and mucosal melanoma subtypes. Subjects with an immune-active profile in the tumor microenvironment or in peripheral blood responded favorably to JS001 treatment. The completion of the current phase I study has led to the initiation of the first prospective anti-PD-1 registration trial in Asia focusing on acral and mucosal melanoma subtypes, representative of the regional disease epidemiology. TRIAL REGISTRATION:Clinical Trial ID: NCT02836795 , registered July 19, 2016, retrospectively registered.

Project description:BACKGROUND:Treatment options for advanced thyroid cancer refractory to standard therapies are limited. The safety and efficacy of pembrolizumab were evaluated in patients with advanced differentiated thyroid cancer expressing programmed death ligand 1 (PD-L1). METHODS:Patients with advanced thyroid cancer were enrolled in the nonrandomized, phase Ib KEYNOTE-028 trial conducted to evaluate safety and antitumor activity of the anti-programmed death 1 (PD-1) antibody pembrolizumab in advanced solid tumors. Key eligibility criteria were advanced papillary or follicular thyroid cancer, failure of standard therapy, and PD-L1 expression in tumor or stroma cells (assessed by immunohistochemistry). Pembrolizumab 10?mg/kg was administered every 2?weeks up to 24?months or until confirmed progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS:Twenty-two patients were enrolled: median age was 61?years; 59% were women; and 68% had papillary carcinoma. Median follow-up was 31?months (range, 7-34?months). Treatment-related adverse events were observed in 18 (82%) patients; those occurring in ?15% of patients were diarrhea (n?=?7) and fatigue (n?=?4). One grade???3 treatment-related adverse event occurred (colitis, grade 3); no treatment-related discontinuations or deaths occurred. Two patients had confirmed partial response, for an ORR of 9% (95% confidence interval [CI], 1-29%); response duration was 8 and 20?months. Median progression-free survival was 7?months (95% CI, 2-14?months); median overall survival was not reached (95% CI, 22?months to not reached). CONCLUSIONS:Results of this phase Ib proof-of-concept study suggest that pembrolizumab has a manageable safety profile and demonstrate evidence of antitumor activity in advanced differentiated thyroid cancer in a minority of patients treated. Further analyses are necessary to confirm these findings. TRIAL REGISTRATION:Clinicaltrials.gov identifier: NCT02054806 . Registered 4 February 2014.

Project description:The efficacy of programmed cell death‑ligand 1 (PD‑L1)/programmed cell death protein 1 (PD‑1) blockade therapy has been demonstrated but is limited in patients with PD‑L1low or immune desert tumors. This limitation can be overcome by combination therapies that include anti‑vascular endothelial growth factor (VEGF) therapy. Such combinations have been investigated in clinical trials for a number of cancer types; however, evidence on the mechanisms underlying their effects in these types of patients is still not sufficient. Therefore, the present study investigated the efficacy and effects on CD8+ T cell and C‑X‑C motif chemokine receptor 3 (CXCR3) ligand expression in tumors by combining anti‑PD‑L1 and anti‑VEGF antibodies using an OV2944‑HM‑1 mouse model with PD‑L1low and immune desert‑like phenotypes. Although the model exhibited anti‑PD‑L1 insensitivity, anti‑PD‑L1 antibody treatment combined with anti‑VEGF antibody inhibited tumor growth compared with anti‑VEGF monotherapy, which itself inhibited tumor growth compared with the control treatment on Day 25. In combination‑treated mice, a higher percentage of CD8+ T cells and higher levels of CXCR3 ligands were observed in tumor tissues compared with those in the anti‑VEGF antibody treatment group, which was not significantly different from control treatment on Day 8. The increase in the intratumoral percentage of CD8+ T cells following the combination treatment was reversed by CXCR3 blocking to the same level as the control. In an anti‑PD‑L1 insensitive model with PD‑L1low and immune desert‑like phenotypes, although anti‑PD‑L1 antibody alone was not effective, anti‑PD‑L1 antibody in combination with anti‑VEGF antibody exhibited antitumor combination efficacy with an increase of CD8+ T cell infiltration, which was suggested to be dependent on the increase of intratumoral CXCR3 ligands. This mechanism could explain the efficacy of anti‑PD‑L1 antibody and anti‑VEGF antibody combination therapy in the clinical setting.

Dataset Information

Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

Publications

Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

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