Abstract:Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the… Show more
“…Phenotypic changes in CD8 T cells in the blood after one cycle of therapy were consistent with T cell reinvigoration and nearly identical in scope to that observed in melanoma patients treated with pembrolizumab. 2 In the tumor, there was an overall increase in CD8 density post-treatment compared to baseline. This change often paralleled upregulation of PD-L1, possibly representing a resistance mechanism.…”
Section: Discussionmentioning
confidence: 88%
“…Change in phenotype as well as the kinetics of this effect on T cells mirrored our previous observations for melanoma patients treated with PD-1 mAb in a separate clinical trial. 2 We found that Ki67+ CD8 T cells after cycle one of therapy were enriched for a phenotype consistent with T cell reinvigoration: Tbet- Eomes± and CD45RA- CD27+, as well as expression of PD-1 and granzyme B (Figure 3b). These data indicate that a systemic CD8 T cell response similar to that observed in response to PD-1 blockade in melanoma patients 2 can also be generated using combination of CD40 activation and CTLA-4 blockade.10.1080/2162402X.2018.1468956-F0003Figure 3.Immune analysis of peripheral lymphocytes.…”
Section: Analysis Of Peripheral T Cell Activationmentioning
confidence: 79%
“…Peripheral blood mononuclear cells (PBMC) were separated from whole heparinized blood using Ficoll Paque (GE Healthcare Life Sciences) and cryopreserved for batch analysis. As previously described, 2 flow cytometry of PBMC was performed with the following antibodies specific for CD3 (OKT-3), CD8 (RPA-T8), CD4 (RPA-T4), CD45RA (MEM-56), CD27 (O323), CD14 (M5E2), CD16 (3G8), CD19 (HIB19) and PD-1 (EH12.2H7) in FACS buffer (HBSS containing 1% FBS and 0.02% sodium azide) at RT for 20 min. Dead cells were excluded by staining for LIVE/DEAD stain (Life Technologies).…”
Section: Methodsmentioning
confidence: 99%
“…1 Nevertheless, many patients still fail to respond clinically to these approaches, yet for PD-1 antibody, immune modulation is observed in nearly every patient. 2 A key goal is to understand the potential of immune modulation that goes beyond CTLA-4 and PD-1.…”
We report long-term clinical outcomes and immune responses observed from a phase 1 trial of agonist CD40 monoclonal antibody (mAb) and blocking CTLA-4 mAb in patients with metastatic melanoma. Twenty-four patients previously untreated with checkpoint blockade were enrolled. The agonistic CD40 mAb CP-870,893 and the CTLA-4 blocking mAb tremelimumab were dosed concomitantly every 3 weeks and 12 weeks, respectively, across four dose combinations. Two patients developed dose-limiting grade 3 immune-mediated colitis that led to the definition of the maximum tolerated dose (MTD). Other immune-mediated toxicity included uveitis (n = 1), hypophysitis (n = 1), hypothyroidism (n = 2), and grade 3 cytokine release syndrome (CRS) (n = 1). The estimated MTD was 0.2 mg/kg of CP-870,893 and 10 mg/kg of tremelimumab. In 22 evaluable patients, the objective response rate (ORR) was 27.3%: two patients (9.1%) had complete responses (CR) and four (18.2%) patients had partial responses (PR). With a median follow-up of 45 months, the median progression-free survival (PFS) was 3.2 months (95% CI, 1.3–5.1 months) and median overall survival (OS) was 23.6 months (95% CI, 11.7–35.5 months). Nine patients are long-term survivors (> 3 years), 8 of whom subsequently received other therapy including PD-1 mAb, surgery, or radiation therapy. Elevated baseline soluble CD25 was associated with shorter OS. Immunologically, treatment was associated with evidence of T cell activation and increased tumor T cell infiltration that was accomplished without therapeutic PD-1/PD-L1 blockade. These results suggest opportunities for immune activation and cancer immunotherapy beyond PD-1.
“…Phenotypic changes in CD8 T cells in the blood after one cycle of therapy were consistent with T cell reinvigoration and nearly identical in scope to that observed in melanoma patients treated with pembrolizumab. 2 In the tumor, there was an overall increase in CD8 density post-treatment compared to baseline. This change often paralleled upregulation of PD-L1, possibly representing a resistance mechanism.…”
Section: Discussionmentioning
confidence: 88%
“…Change in phenotype as well as the kinetics of this effect on T cells mirrored our previous observations for melanoma patients treated with PD-1 mAb in a separate clinical trial. 2 We found that Ki67+ CD8 T cells after cycle one of therapy were enriched for a phenotype consistent with T cell reinvigoration: Tbet- Eomes± and CD45RA- CD27+, as well as expression of PD-1 and granzyme B (Figure 3b). These data indicate that a systemic CD8 T cell response similar to that observed in response to PD-1 blockade in melanoma patients 2 can also be generated using combination of CD40 activation and CTLA-4 blockade.10.1080/2162402X.2018.1468956-F0003Figure 3.Immune analysis of peripheral lymphocytes.…”
Section: Analysis Of Peripheral T Cell Activationmentioning
confidence: 79%
“…Peripheral blood mononuclear cells (PBMC) were separated from whole heparinized blood using Ficoll Paque (GE Healthcare Life Sciences) and cryopreserved for batch analysis. As previously described, 2 flow cytometry of PBMC was performed with the following antibodies specific for CD3 (OKT-3), CD8 (RPA-T8), CD4 (RPA-T4), CD45RA (MEM-56), CD27 (O323), CD14 (M5E2), CD16 (3G8), CD19 (HIB19) and PD-1 (EH12.2H7) in FACS buffer (HBSS containing 1% FBS and 0.02% sodium azide) at RT for 20 min. Dead cells were excluded by staining for LIVE/DEAD stain (Life Technologies).…”
Section: Methodsmentioning
confidence: 99%
“…1 Nevertheless, many patients still fail to respond clinically to these approaches, yet for PD-1 antibody, immune modulation is observed in nearly every patient. 2 A key goal is to understand the potential of immune modulation that goes beyond CTLA-4 and PD-1.…”
We report long-term clinical outcomes and immune responses observed from a phase 1 trial of agonist CD40 monoclonal antibody (mAb) and blocking CTLA-4 mAb in patients with metastatic melanoma. Twenty-four patients previously untreated with checkpoint blockade were enrolled. The agonistic CD40 mAb CP-870,893 and the CTLA-4 blocking mAb tremelimumab were dosed concomitantly every 3 weeks and 12 weeks, respectively, across four dose combinations. Two patients developed dose-limiting grade 3 immune-mediated colitis that led to the definition of the maximum tolerated dose (MTD). Other immune-mediated toxicity included uveitis (n = 1), hypophysitis (n = 1), hypothyroidism (n = 2), and grade 3 cytokine release syndrome (CRS) (n = 1). The estimated MTD was 0.2 mg/kg of CP-870,893 and 10 mg/kg of tremelimumab. In 22 evaluable patients, the objective response rate (ORR) was 27.3%: two patients (9.1%) had complete responses (CR) and four (18.2%) patients had partial responses (PR). With a median follow-up of 45 months, the median progression-free survival (PFS) was 3.2 months (95% CI, 1.3–5.1 months) and median overall survival (OS) was 23.6 months (95% CI, 11.7–35.5 months). Nine patients are long-term survivors (> 3 years), 8 of whom subsequently received other therapy including PD-1 mAb, surgery, or radiation therapy. Elevated baseline soluble CD25 was associated with shorter OS. Immunologically, treatment was associated with evidence of T cell activation and increased tumor T cell infiltration that was accomplished without therapeutic PD-1/PD-L1 blockade. These results suggest opportunities for immune activation and cancer immunotherapy beyond PD-1.
“…These strategies incorporate immune status and tumor burden. A recent study found that the magnitude of reinvigorated, exhausted CD8+ T-cells in the peripheral blood on treatment with pembrolizumab in relationship to the pretreatment tumor burden correlated with clinical response, suggesting a clinically accessible on-treatment predictor of response (76). A more comprehensive strategy called the "cancer immunogram" incorporating the tumor mutational load, general immune status of the patient, immune cell infiltration of the tumor, absence of checkpoints, absence of soluble inhibitors, absence of inhibitory metabolism, and sensitivity to immune effectors is also under development (77).…”
Section: Biomarkers Of Checkpoint Inhibitor Activitymentioning
Abstract:Immune checkpoint blockade has revolutionized the treatment of patients with advanced melanoma and many other cancers. Blockade of inhibitory receptors, CTLA-4 and PD-1, enhances T-cell-mediated antitumor immune responses, leading to improved survival and durable responses in patients. Based on their mechanism of action, immune checkpoint inhibitors can also induce immune-related adverse events that require careful monitoring and prompt treatment. Despite these successes, only a fraction of patients benefit from immune checkpoint blockade. Basic science approaches and clinical experience are defining predictive biomarkers to identify patients most likely to respond to therapy as well as mechanisms of resistance that limit responses in certain tumors or shorten the duration of response. New approaches and combination therapies are under development to broaden the clinical impact of immune checkpoint blockade by overcoming resistance to therapy and limiting adverse events.
Immune checkpoint blockade with anti-PD-1 antibodies is showing great promise for patients with metastatic melanoma and other malignancies, but despite good responses by some patients who achieve partial or complete regression, many others still do not respond. Here, we sought peripheral blood T-cell biomarker candidates predicting treatment outcome in 75 stage IV melanoma patients treated with anti-PD-1 antibodies. We investigated associations with clinical response, progression-free survival (PFS) and overall survival (OS). Univariate analysis of potential biological confounders and known biomarkers, and a multivariate model, was used to determine statistical independence of associations between candidate biomarkers and clinical outcomes. We found that a lower than median frequency of peripheral PD-1+CD56+ T-cells was associated with longer OS (p = 0.004), PFS (p = 0.041) and superior clinical benefit (p = 0.009). However, neither frequencies of CD56-CD4+ nor CD56-CD8+ T-cells, nor of the PD-1+ fraction within the CD4 or CD8 subsets was associated with clinical outcome. In a multivariate model with known confounders and biomarkers only the M-category (HR, 3.11; p = 0.007) and the frequency of PD-1+CD56+ T-cells (HR, 2.39; p = 0.028) were identified as independent predictive factors for clinical outcome under PD-1 blockade. Thus, a lower than median frequency of peripheral blood PD-1+CD56+ T-cells prior to starting anti-PD-1 checkpoint blockade is associated with superior clinical response, longer PFS and OS of stage IV melanoma patients.
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