Programmed death 1 immune checkpoint inhibitors.

Programmed death 1 (PD-1) is an immune checkpoint that provides inhibitory signals to the immune system in order to modulate the activity of T cells in peripheral tissues and maintain self-tolerance in the setting of infection and inflammation. In cancer, the immune checkpoints are exploited so that the tumor cells are able to evade the immune system. Immune checkpoint inhibitors are a type of cancer immunotherapy that targets pathways such as PD-1 in order to reinvigorate and enhance the immune response against tumor cells. The US Food and Drug Administration (FDA) has approved 2 PD-1 inhibitors, nivolumab and pembrolizumab, and several others are under investigation. Although PD-1 inhibitors have demonstrated activity in many different types of malignancies, FDA approval has been granted only in melanoma and in non-small cell lung cancer (NSCLC). Identifying biomarkers that can predict response to PD-1 inhibitors is critical to maximizing the benefit of these agents. Future directions for PD-1 inhibitors include investigation of combination therapies, use in malignancies other than melanoma and NSCLC, and refinement of biomarkers.

Parallel phase Ib studies of two schedules of buparlisib (BKM120) plus carboplatin and paclitaxel (q21 days or q28 days) for patients with advanced solid tumors.

PURPOSE: Phosphatidylinositol-3-kinase I (PI3K) inhibition sensitizes a wide range of cancer cell lines to platinum/taxane-based chemotherapy. This phase I study combines buparlisib, a pan-class 1A PI3K inhibitor, with two schedules of carboplatin and paclitaxel for patients with advanced solid tumors (ClinicalTrials.gov, NCT01297452). METHODS: There were two regimens: Group 1 received carboplatin AUC 5 and paclitaxel 175 mg/m(2), on day 1 of a 21-day cycle with pegfilgrastim support; Group 2 received carboplatin AUC 5 (day 1) and paclitaxel 80 mg/m(2) (days 1, 8, and 15) on a 28-day cycle without growth factor support. In both groups, three dose levels of buparlisib were explored: 50, 80, and 100 mg/day. Primary endpoint was to identify recommended phase II doses of buparlisib in both groups. RESULTS: Thirty subjects enrolled, 16 in Group 1 and 14 in Group 2. The DLTs were elevated alkaline phosphatase (n = 1) and uncomplicated neutropenia (n = 2). The median numbers of cycles were 5 (Group 1) and 6 (Group 2). The MTDs for buparlisib were 100 mg/day in Group 1 and 80 mg/day in Group 2. Among 25 patients with measurable disease, the confirmed objective response rate was 20% (one complete response, four partial responses). Among three patients with known loss of PTEN expression, all derived clinical benefit from treatment. CONCLUSION: The addition of buparlisib to carboplatin + paclitaxel was well tolerated, and preliminary activity was notable against tumors with loss of PTEN expression.

Phase I study of flavopiridol with oxaliplatin and fluorouracil/leucovorin in advanced solid tumors.

PURPOSE: Flavopiridol, a cyclin-dependent kinase inhibitor, has promising clinical activity when combined with chemotherapy. Preclinical data indicate that flavopiridol enhances oxaliplatin- and fluorouracil (5FU)-induced apoptosis in a sequence-dependent manner. EXPERIMENTAL DESIGN: We conducted a phase I trial of flavopiridol + FOLFOX (folinic acid, 5FU, and oxaliplatin) for advanced solid tumors. Flavopiridol was administered every 2 weeks with oxaliplatin before 5FU, based on sequence-dependent growth inhibition. Flavopiridol pharmacokinetics and p53 status were evaluated. RESULTS: Forty-eight patients were treated on study. With dose escalation of oxaliplatin (85 mg/m(2)) and 5FU (2,400 mg/m(2)), dose-limiting toxicities included hyponatremia, thrombocytopenia, and neutropenia. 5FU was subsequently reduced to allow for dose escalation of flavopiridol. Dose-limiting toxicities with escalation of flavopiridol were nausea, vomiting, and neutropenia. The maximum tolerated dose was 70 mg/m(2) flavopiridol, 85 mg/m(2) oxaliplatin, and 1,800 mg/m(2) 5FU continuous infusion over 48 hours. Clinical activity was noted in platinum-refractory germ cell tumors: 3 of 9 (33%) evaluable patients showed a partial response on imaging and 7 of 10 (70%) had a decline in serum tumor markers. Responses were also observed in pancreatic, gastric, and sweat gland tumors. Flavopiridol pharmacokinetics had significant interpatient variability. At the maximum tolerated dose, tumor samples were p53 mutant (>30% positive cells) for responders and p53 wild-type for nonresponders. CONCLUSIONS: Flavopiridol with FOLFOX is a safe and tolerable regimen. Promising clinical activity was seen across tumor types. Encouraging results in the platinum-refractory germ cell tumor population has prompted a phase II trial that is currently open for accrual.

Patients undergoing treatment for pancreatic adenocarcinoma can mount an effective immune response to vaccinations.

BACKGROUND: Immunotherapy has been proposed as a novel treatment for pancreatic cancer. However, patients with pancreatic cancer have been observed to have depressed immune responses, suggesting that immunotherapy might have limited utility in this group of patients. We sought to determine whether patients undergoing postresection or primary medical treatment for pancreatic adenocarcinoma were immunocompetent. METHODS: We enrolled patients with pancreatic adenocarcinoma scheduled for postresection or primary chemotherapy and/or radiation therapy. At the initiation of therapy, the patients had an anergy panel placed and baseline blood work performed. During the first week of treatment, patients received tetanus toxoid (TT), Haemophilus influenzae and Pneumococcus vaccines. Twelve weeks after vaccine administration, IgG titers against the 3 administered vaccines were done, and lymphocyte proliferation assays in response to TT were performed. RESULTS: Eighteen patients were originally enrolled, and 14 patients completed all elements of the trial. Anergy panel responses were obtained for 15 patients who comprised the final study group; both pre- and postvaccination data were available for 14 patients. Nine of 15 patients demonstrated at least a 10-mm induration in response to mumps or Candida antigen (60% response rate, 95% confidence interval (CI) 32-84%). Thirteen of 14 patients demonstrated a > or =3-fold increase in IgG against one or more vaccines (93% response rate, 95% CI 66-100%). Nine of 14 patients (64% response rate, 95% CI 35-87%) demonstrated at least a 3-fold rise of lymphocyte proliferation against TT. CONCLUSIONS: Patients with pancreatic cancer were capable of mounting effective cellular and humoral responses to standard vaccines. These data suggest that immunotherapy for pancreatic cancer may be feasible and merits further investigation.