Ben C. Creelan

Indoleamine 2,3-dioxygenase activity and clinical outcome following induction chemotherapy and concurrent chemoradiation in Stage III non-small cell lung cancer

Indoleamine 2,3-dioxygenase (IDO) has recently been proposed to account for tumor-induced immunosuppression by influencing the conversion of tryptophan (Trp) into kynurenine (Kyn). The objective of our study was to correlate IDO activity with disease outcome in non-small cell lung cancer (NSCLC) patients treated with multimodal combination therapy. In a single-arm Phase II trial involving induction gemcitabine and carboplatin followed by concurrent paclitaxel, carboplatin and 74 Gy thoracic radiation in stage III NSCLC patients, plasma was drawn at baseline, post-induction, and post-concurrent therapy. The mean plasma Kyn/Trp ratio was used as a surrogate indicator of IDO activity. The 33 participants were distributed as follows: 15 females, 18 males; median age = 62; median overall survival (OS) = 22.4 (95% CI 19.3–25.1) months; median progression-free survival (PFS) = 11.5 (95% CI 6.7–16.3) months. The mean Kyn/Trp ratio at baseline (4.5 ± 2.8) was higher than that of healthy controls (2.9 ± 1.9, p = 0.03) and increased after induction therapy (5.2 ± 3.2, p = 0.08) and chemoradiation (5.8 ± 3.9, p = 0.01). The post-treatment Kyn/Trp ratio and radiologic responses were not significantly associated at any time point. No significant correlation was found between baseline Kyn/Trp ratios and OS (HR = 1.1, 95% CI 0.45–2.5) or PFS (HR = 0.74, 95% CI 0.30–1.82). A post-induction chemotherapy increase in IDO activity portended worse OS (HR = 0.43, 95% CI 0.19–0.95, p = 0.037) and PFS (HR = 0.47, 95% CI 0.22–1.0, p = 0.055). This observed increase in IDO transcription may be a means for tumors to evade immunosurveillance.

Outcomes targeting the PD-1/PD-L1 axis in conjunction with stereotactic radiation for patients with non-small cell lung cancer brain metastases.

Anti-PD-1/PD-L1 therapies have demonstrated activity in patients with advanced stage non-small cell lung cancer (NSCLC). However, little is known about the safety and feasibility of patients receiving anti-PD-1/PD-L1 therapy and stereotactic radiation for the treatment of brain metastases. Data were analyzed retrospectively from NSCLC patients treated with stereotactic radiation either before, during or after anti-PD-1/PD-L1 therapy with nivolumab (anti-PD-1) or durvalumab (anti-PD-L1). Seventeen patients treated with stereotactic radiosurgery (SRS) or fractionated stereotactic radiation therapy (FSRT) to 49 brain metastases over 21 sessions were identified. Radiation was administered prior to, during and after anti-PD-1/PD-L1 therapy in 22 lesions (45%), 13 lesions (27%), and 14 lesions (29%), respectively. The 6 months Kaplan–Meier (KM) distant brain control rate was 48% following stereotactic radiation. Six and 12 month KM rates of OS from the date of stereotactic radiation and the date of cranial metastases diagnosis were 48/41% and 81/51%, respectively. The 6 month rate of distant brain control following stereotactic radiation for patients treated with stereotactic radiation during or prior to anti-PD-1/PD-L1 therapy was 57% compared to 0% among patients who received anti-PD-1/PD-L1 therapy before stereotactic radiation (p = 0.05). A Karnofsky Performance Status (KPS) of <90 was found to be predictive of worse OS following radiation treatment on both univariate and multivariate analyses (MVA, p = 0.01). In our series, stereotactic radiation to NSCLC brain metastases was well tolerated in patients who received anti-PD-1/PD-L1 therapy. Prospective evaluation to determine how these two modalities can be used synergistically to improve distant brain control and OS is warranted.

Phase II trial of a GM-CSF-producing and CD40L-expressing bystander cell line combined with an allogeneic tumor cell-based vaccine for refractory lung adenocarcinoma

We created a vaccine in which irradiated allogeneic lung adenocarcinoma cells are combined with a bystander K562 cell line transfected with hCD40L and hGM-CSF. By recruiting and activating dendritic cells, we hypothesized that the vaccine would induce tumor regression in metastatic lung adenocarcinoma. Intradermal vaccine was given q14 days×3, followed by monthly ×3. Cyclophosphamide (300 mg/m2 IV) was administered before the first and fourth vaccines to deplete regulatory T cells. All-trans retinoic acid was given (150/mg/m2/d) after the first and fourth vaccines to enhance dendritic cell differentiation. Twenty-four participants were accrued at a single institution from October 2006 to June 2008, with a median age 64 years and median of 4 previous lines of systemic therapy. A total of 101 vaccines were administered. Common toxicities were headache (54%) and site reaction (38%). No radiologic responses were observed. Median overall survival was 7.9 months and median progression-free survival was 1.7 months. Of 14 patients evaluable for immunological study, 5 had peptide-induced CD8+ T-cell activation after vaccination. Overall, vaccine administration was feasible in an extensively pretreated population of metastatic lung cancer. Despite a suggestion of clinical activity in the subset with immune response, the trial did not meet the primary endpoint of inducing radiologic tumor regression.

Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors

Background Omaveloxolone is a semisynthetic oleanane triterpenoid that potently activates Nrf2 with subsequent antioxidant function. We conducted a first-in-human Phase I clinical trial (NCT02029729) with the primary objectives to determine the appropriate dose for Phase II studies, characterize pharmacokinetic and pharmacodynamic parameters, and assess antitumor activity. Methods Omaveloxolone was administered orally once daily continuously in a 28-day cycle for patients with stage 4 relapsed/refractory melanoma or non-small cell lung cancer. An accelerated titration design was employed until a grade 2-related adverse event (AE) occurred. A standard 3+3 dose escalation was employed. Single-dose and steady-state plasma pharmacokinetics of the drug were characterized. Downstream Nrf2 activation was assessed in peripheral blood mononuclear cells by quantification of target gene mRNA expression. Results Omaveloxolone was tested at four dose levels up to 15 mg given orally once daily. No dose-limiting toxicities were detected, and the maximum tolerated dose was not determined. All drug-related AEs were either grade 1 or 2 in severity, and none required clinical action. The most common drug-related AEs were elevated alkaline phosphatase (18%) and anemia (18%). No drug interruptions or reductions were required. Omaveloxolone was rapidly absorbed and exhibited proportional increases in exposure across dose levels. With some exceptions, an overall trend toward time-dependent and dose-dependent activation of Nrf2 antioxidant genes was observed. No confirmed radiologic responses were seen, although one lung cancer subject did have stable disease exceeding 1 year. Conclusions Omaveloxolone has favorable tolerability at biologically active doses, although this trial had a small sample size which limits definitive conclusions. These findings support further investigation of omaveloxolone in cancer.

Immunotherapy in lung cancer: "b7-bombers" and other new developments.

Several recent immunotherapy agents have exhibited exceptional activity, and their eventual approval for use in lung cancer appears plausible. The immune checkpoint proteins, such as the B7 superfamily, are becoming increasingly relevant targets for therapeutic inhibition. Tumor vaccines hold the potential to deliver durable responses that are specific for tumor antigen, with favorable adverse effect profiles. Several vaccine trials are accruing more patients than any previous lung cancer trials and are designed to select a specific population based on a predefined, scientifically justified biomarker. These emerging immune treatments may hold great potential for the systemic treatment of lung cancers.

Progressive hypoventilation due to mixed CD8 + and CD4 + lymphocytic polymyositis following tremelimumab - durvalumab treatment

BackgroundThe combination of CTLA-4 and PD-L1 inhibitors has a manageable adverse effect profile, although rare immune-related adverse events (irAE) can occur.Case presentationWe describe an autoimmune polymyositis following a partial response to combination tremelimumab and durvalumab for the treatment of recurrent lung adenocarcinoma. Radiography revealed significant reduction in all metastases; however, the patient developed progressive neuromuscular hypoventilation due to lymphocytic destruction of the diaphragmatic musculature. Serologic testing revealed a low level of de novo circulating antibodies against striated muscle fiber. Immunohistochemistry revealed type II muscle fiber atrophy with a mixed CD8+ and CD4+ lymphocyte infiltrate, indicative of inflammatory myopathy.ConclusionsThis case supports the hypothesis that muscle tissue is a target for lymphocytic infiltration in immune checkpoint inhibitor-associated polymyositis. Further insights into the autoimmune mechanism of PM will hopefully contribute to the prevention and treatment of this phenomenon.Background The combination of CTLA-4 and PD-L1 inhibitors has a manageable adverse effect profile, although rare immune-related adverse events (irAE) can occur. Case presentation We describe an autoimmune polymyositis following a partial response to combination tremelimumab and durvalumab for the treatment of recurrent lung adenocarcinoma. Radiography revealed significant reduction in all metastases; however, the patient developed progressive neuromuscular hypoventilation due to lymphocytic destruction of the diaphragmatic musculature. Serologic testing revealed a low level of de novo circulating antibodies against striated muscle fiber. Immunohistochemistry revealed type II muscle fiber atrophy with a mixed CD8+ and CD4+ lymphocyte infiltrate, indicative of inflammatory myopathy. Conclusions This case supports the hypothesis that muscle tissue is a target for lymphocytic infiltration in immune checkpoint inhibitor-associated polymyositis. Further insights into the autoimmune mechanism of PM will hopefully contribute to the prevention and treatment of this phenomenon. Electronic supplementary material The online version of this article (doi:10.1186/s40425-017-0258-x) contains supplementary material, which is available to authorized users.

Induction chemoradiotherapy versus chemotherapy alone for superior sulcus lung cancer

OBJECTIVES Although treatment of superior sulcus tumors with induction chemoradiotherapy (CRT) followed by surgery employed in the Intergroup INT-0160 trial is widely adopted as a standard of care, there may be significant associated morbidity and mortality. We describe our experience using standard and alternative induction regimens to assess survival rates and treatment toxicity in these patients. MATERIALS AND METHODS Electronic medical records of all patients who underwent multimodality treatment including resection of lung cancer invading the superior pulmonary sulcus between 1994 and 2016 were retrospectively reviewed. Multivariable Cox Proportional Hazards model was constructed. RESULTS Of 102 consecutive patients, 53 (52%) underwent induction CRT, 34 (33%) underwent induction chemotherapy only (Ch) followed by adjuvant radiotherapy, and 15 (15%) underwent no induction therapy followed by adjuvant therapy. There were 2 postoperative deaths (1.9%). To date, 42 patients are alive with a median follow-up 72.5 months. Overall 5-year survival rate was 45.4%. Survival was significantly influenced by age, FEV1, positive resection margins, surgical complications, but not the induction regimen. CRT resulted in higher complete pathological response rate than Ch: 38% vs. 3% (p < 0.001). CRT was associated with higher post-operative re-intubation rate: 13% vs. 0% (p = 0.03). CONCLUSIONS Our single-institutional experience indicated that while induction CRT produced greater complete pathological response than Ch, it also increased the risk of post-operative complications. With careful patient selection, induction Ch followed by adjuvant radiotherapy may provide comparable survival outcomes to induction CRT. Since induction Ch is associated with lower risk of complications, it may be a particularly desirable choice for patients with impaired performance status.

The Current Understanding of the Endocrine Effects From Immune Checkpoint Inhibitors and Recommendations for Management

Abstract Clinical trials in the past decade have established the antitumor effects of immune checkpoint inhibition as a revolutionary treatment for cancer. Namely, blocking antibodies to cytotoxic T-lymphocyte antigen 4 and programmed death 1 or its ligand have reached routine clinical use. Manipulation of the immune system is not without side effects, and autoimmune toxicities often known as immune-related adverse events (IRAEs) are observed. Endocrine IRAEs, such as hypophysitis, thyroid dysfunction, and insulin-dependent diabetes mellitus, can present with unique profiles that are not seen with the use of traditional chemotherapeutics. In this Review, we discuss the current hypotheses regarding the mechanism of these endocrinopathies and their clinical presentations. Further, we suggest guidelines and algorithms for patient management and future clinical trials to optimize the detection and treatment of immune checkpoint–related endocrinopathies.

A phase I/randomized phase II study of GM.CD40L vaccine in combination with CCL21 in patients with advanced lung adenocarcinoma

The GM.CD40L vaccine, which recruits and activates dendritic cells, migrates to lymph nodes, activating T cells and leading to systemic tumor cell killing. When combined with the CCL21 chemokine, which recruits T cells and enhances T-cell responses, additive effects have been demonstrated in non-small cell lung cancer mouse models. Here, we compared GM.CD40L versus GM.CD40L plus CCL21 (GM.CD40L.CCL21) in lung adenocarcinoma patients with ≥ 1 line of treatment. In this phase I/II randomized trial (NCT01433172), patients received intradermal vaccines every 14 days (3 doses) and then monthly (3 doses). A two-stage minimax design was used. During phase I, no dose-limiting toxicities were shown in three patients who received GM.CD40L.CCL21. During phase II, of evaluable patients, 5/33 patients (15.2%) randomized for GM.DCD40L (p = .023) and 3/32 patients (9.4%) randomized for GM.DCD40L.CCL21 (p = .20) showed 6-month progression-free survival. Median overall survival was 9.3 versus 9.5 months with GM.DCD40L versus GM.DCD40L.CCL21 (95% CI 0.70–2.25; p = .44). For GM.CD40L versus GM.CD40L.CCL21, the most common treatment-related adverse events (TRAEs) were grade 1/2 injection site reaction (51.4% versus 61.1%) and grade 1/2 fatigue (35.1% versus 47.2%). Grade 1 immune-mediated TRAEs were isolated to skin. No patients showed evidence of pseudo-progression or immune-related TRAEs of grade 1 or greater of pneumonitis, endocrinopathy, or colitis, and none discontinued treatment due to toxicity. Although we found no significant associations between vaccine immunogenicity and outcomes, in limited biopsies, one patient treated with GMCD40L.CCL21 displayed abundant tumor-infiltrating lymphocytes. This possible effectiveness warrants further investigation of GM.CD40L in combination approaches.

Early2 factor (E2F) deregulation is a prognostic and predictive biomarker in lung adenocarcinoma

Clinicians routinely prescribe adjuvant chemotherapy (ACT) for resected non-small cell lung cancer patients. However, ACT only improves five-year disease-free survival in stage I-III non-small cell lung cancer by 5-15%, with most patients deriving no benefit. Herein, deregulation of the E2F pathway was explored as a biomarker in lung adenocarcinoma patients. An E2F pathway scoring system, based on 74 E2F-regulated genes, was trained for RNA from two platforms: fresh-frozen (FF) or formalin-fixed paraffin-embedded (FFPE) tissues. The E2F score was tested as a prognostic biomarker in five FF-based cohorts and two FFPE-based cohorts. The E2F score was tested as a predictive biomarker in two randomized clinical trials; JBR10 and the NATCH (Neo-Adjuvant Taxol-Carboplatin Hope) trial. The E2F score was prognostic in untreated patients in all seven datasets examined (p < 0.05). Stage-specific analysis of combined cohorts demonstrated that the E2F score was prognostic in stage I patients (p = 0.0495 to <0.001; hazard ratio, HR, =2.04- 2.22) with a similar trend in other stages. The E2F score was strongly predictive in stage II patients from the two combined randomized clinical trials with a significant differential treatment effect (p = 0.015). Specifically, ACT improved survival in stage II patients with high E2F (p = 0.01; HR= 0.21). The 5-year survival increased from 18% to 81%. In contrast, in patients with low E2F, 5-year survival was 57% in untreated patients and 41% in ACT-treated patients with a HR of 1.55 (p = 0.47). In summary, the E2F score provides valuable prognostic information for Stage I and predictive information for Stage II lung adenocarcinoma patients and should be further explored as a decision support tool for their treatment.