Search

Purpose: Multisite stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) has demonstrated safety in advanced solid tumors (ASTs). However, no studies have examined the relationships between irradiated tumor response, SBRT-induced tumor gene expression, and overall survival (OS)., Patients and Methods: Patients with AST received SBRT (30-50 Gy in 3-5 fractions) to two to four metastases followed by pembrolizumab (200 mg i.v. every 3 weeks). SBRT was prescribed to a maximum tumor volume of 65 mL. Small metastases received the complete prescribed coverage (complete-Rx), while larger metastases received partial coverage (partial-Rx). Treated metastasis control (TMC) was defined as a lack of progression for an irradiated metastasis. Landmark analysis was used to assess the relationship between TMC and OS. Thirty-five biopsies were obtained from 24 patients: 19 pre-SBRT and 16 post-SBRT (11 matched) prior to pembrolizumab and were analyzed via RNA microarray., Results: Sixty-eight patients (139 metastases) were enrolled with a median follow-up of 10.4 months. One-year TMC was 89.5% with no difference between complete-Rx or partial-Rx. On multivariable analysis, TMC was independently associated with a reduced risk for death (HR, 0.36; 95% confidence interval, 0.17-0.75; P = 0.006). SBRT increased expression of innate and adaptive immune genes and concomitantly decreased expression of cell cycle and DNA repair genes in the irradiated tumors. Elevated post-SBRT expression of DNASE1 correlated with increased expression of cytolytic T-cell genes and irradiated tumor response., Conclusions: In the context of SBRT+P, TMC independently correlates with OS. SBRT impacts intratumoral immune gene expression associated with TMC. Randomized trials are needed to validate these findings., (©2020 American Association for Cancer Research.)

Background: Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor. Metformin may potentiate mTOR inhibition by sirolimus while mitigating its adverse effects. We conducted a pilot study to test this hypothesis., Methods: Patients with advanced solid tumor were treated with sirolimus for 7 days followed by randomization to either sirolimus with metformin (Arm A) or sirolimus (Arm B) until day 21. From day 22 onwards, all patients received sirolimus and metformin. The primary aim was to compare the change in phospho-p70S6K (pp70S6K) in peripheral blood mononuclear cells (PBMC) from day 8 to day 22 using a two-sample t test. Secondary aims were objective response rate, toxicity, and other serum pharmacodynamic biomarkers (e.g., fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, and leptin)., Results: 24 patients were enrolled, with 18 evaluable for the primary endpoint. There was no significant difference in mean change in pp70S6K in arm A vs. arm B (- 0.12 vs. - 0.16; P = 0.64). Similarly, there were no significant differences in other serum pharmacodynamic biomarkers. There were no partial responses. There were no dose-limiting or unexpected toxicities., Conclusions: Adding metformin to sirolimus, although well tolerated, was not associated with significant changes in pp70S6K in PBMC or other serum pharmacodynamic biomarkers., Impact: Combining metformin with sirolimus did not improve mTOR inhibition.

Adoptively transferred CD8 + T cells can stabilize the size of solid tumors over long periods of time by exclusively recognizing antigen cross-presented on tumor stroma. However, these tumors eventually escape T-cell-mediated growth control. The aim of this study was to eradicate such persistent cancers. In our model, the SIYRYYGL antigen is expressed by cancer cells that lack the MHC-I molecule K b needed for direct presentation, but the antigen is picked up and cross-presented by tumor stroma. A single injection of antigen-specific 2C CD8 + T cells caused long-term inhibition of tumor growth, but without further intervention, tumors started to progress after approximately 3 months. Escape was associated with reduced numbers of circulating 2C cells. Tumor-infiltrating 2C cells produced significantly less TNFα and expressed more of the "exhaustion" markers PD-1 and Tim-3 than T cells from lymphoid organs. High-dose local ionizing radiation, depletion of myeloid-derived suppressor cells, infusions of additional 2C cells, and antibodies blocking PD-L1 did not prevent tumor escape. In contrast, adoptive transfer of allogeneic CD4 + T cells restored the numbers of circulating Ag-specific CD8 + T cells and their intratumoral function, resulting in tumor eradication. These CD4 + T cells had no antitumor effects in the absence of CD8 + T cells and recognized the alloantigen cross-presented on tumor stroma. CD4 + T cells might also be effective in cancer patients when PD-1/PD-L1 blockade does not rescue intratumoral CD8 + T-cell function and tumors persist. Cancer Immunol Res; 5(2); 127-36. ©2017 AACR., (©2017 American Association for Cancer Research.)

Purpose: The risk of severe neutropenia from treatment with irinotecan is related in part to UGT1A1*28, a variant that reduces the elimination of SN-38, the active metabolite of irinotecan. We aimed to identify the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of irinotecan in patients with advanced solid tumors stratified by the *1/*1, *1/*28, and *28/*28 genotypes., Patients and Methods: Sixty-eight patients received an intravenous flat dose of irinotecan every 3 weeks. Forty-six percent of the patients had the *1/*1 genotype, 41% had the *1/*28 genotype, and 13% had the *28/*28 genotype. The starting dose of irinotecan was 700 mg in patients with the *1/*1 and *1/*28 genotypes and 500 mg in patients with the *28/*28 genotype. Pharmacokinetic evaluation was performed at cycle 1., Results: In patients with the *1/*1 genotype, the MTD was 850 mg (four DLTs per 16 patients), and 1,000 mg was not tolerated (two DLTs per six patients). In patients with the *1/*28 genotype, the MTD was 700 mg (five DLTs per 22 patients), and 850 mg was not tolerated (four DLTs per six patients). In patients with the *28/*28 genotype, the MTD was 400 mg (one DLT per six patients), and 500 mg was not tolerated (three DLTs per three patients). The DLTs were mainly myelosuppression and diarrhea. Irinotecan clearance followed linear kinetics. At the MTD for each genotype, dosing by genotype resulted in similar SN-38 areas under the curve (AUCs; r(2) = 0.0003; P = .97), but the irinotecan AUC was correlated with the actual dose (r(2) = 0.39; P < .001). Four of 48 patients with disease known to be responsive to irinotecan achieved partial response., Conclusion: The UGT1A1*28 genotype can be used to individualize dosing of irinotecan. Additional studies should evaluate the effect of genotype-guided dosing on efficacy in patients receiving irinotecan., (© 2014 by American Society of Clinical Oncology.)

Hypertension after treatment with vascular endothelial growth factor (VEGF) receptor inhibitors is associated with superior treatment outcomes for advanced cancer patients. To determine whether increased sorafenib doses cause incremental increases in blood pressure (BP), we measured 12-h ambulatory BP in 41 normotensive advanced solid tumor patients in a randomized dose-escalation study. After 7 days' treatment (400 mg b.i.d.), mean diastolic BP (DBP) increased in both study groups. After dose escalation, group A (400 mg t.i.d.) had marginally significant further increase in 12-h mean DBP (P = 0.053), but group B (600 mg b.i.d.) did not achieve statistically significant increases (P = 0.25). Within groups, individuals varied in BP response to sorafenib dose escalation, but these differences did not correlate with changes in steady-state plasma sorafenib concentrations. These findings in normotensive patients suggest BP is a complex pharmacodynamic biomarker of VEGF inhibition. Patients have intrinsic differences in sensitivity to sorafenib's BP-elevating effects.

Inhibition of vascular endothelial growth factor (VEGF) signaling increases red blood cell (RBC) counts, and erythropoiesis markers have been proposed to guide antiangiogenic therapy in humans. We analyzed RBC measurements in patients enrolled in three studies: a phase II trial of axitinib in thyroid cancer; a study of sorafenib in advanced solid tumors; and a randomized trial of fluorouracil, hydroxyurea, and radiation with and without bevacizumab for head and neck cancer. In the sorafenib trial, plasma erythropoietin concentrations were measured at baseline, day 8, and day 35. Over the first 84 days of treatment, RBC counts increased for each day on sorafenib (2.7 M/μL [95% confidence interval (CI), 1.5-3.9]) and axitinib (4.3 M/μL [95% CI, 2.2-6.5]). RBCs declined over the first 68 days of cytotoxic chemoradiotherapy alone (-12.8 M/μL per day [95% CI, -15.7 to -9.8]) but less so with added bevacizumab (-7.2 M/μL per day [95% CI, -9.5 to -4.9]). Erythropoietin levels increased, on average, by 9.5 mIU/mL between day 8 and day 35 of sorafenib exposure. No significant relationships between elevations in RBCs and changes in volume status or blood pressure or between elevations in erythropoietin and smoking status were found. VEGF signaling inhibition is associated with increased RBC and erythropoietin production in humans. The effects of these changes are subtle at physiologic doses and are unlikely to be clinically useful biomarkers for guiding the administration of or predicting treatment responses to VEGF pathway inhibitors.

Purpose: Irinotecan and thalidomide are commonly administered antineoplastic drugs. Combination treatment may potentiate their antitumor effect and protect against irinotecan's intestinal toxicity. We investigated whether thalidomide can modulate the pharmacokinetics of irinotecan and metabolites., Methods: The study employed a crossover design in which advanced solid tumor patients were randomized to two arms and treated with irinotecan 350 mg/m(2) intravenously (IV) every 3 weeks and thalidomide orally (p.o.) 400 mg daily. Pharmacokinetic data when irinotecan was administered as a single agent in each arm were compared to data when the two study agents were co-administered using paired t tests. Eighty percent and 90% confidence intervals for the true difference were also calculated., Results: The differences in pharmacokinetic parameters and metabolic markers after thalidomide administration were small and unlikely to be clinically significant. With the exception of APC T (1/2), none of the upper confidence limits exceeds a 50% increase., Conclusions: This study did not find any clinically meaningful effects of thalidomide on the pharmacokinetics of irinotecan or its metabolites.

Purpose: Hypertension is a mechanism-based toxicity of sorafenib and other cancer therapeutics that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. This prospective, single-center, cohort study characterized ambulatory blood pressure monitoring as an early pharmacodynamic biomarker of VEGF signaling pathway inhibition by sorafenib., Experimental Design: Fifty-four normotensive advanced cancer patients underwent 24-hour ambulatory blood pressure monitoring before and between days 6 and 10 of sorafenib therapy. After blood pressure changes were detected among the first cohort within 10 days, ambulatory blood pressure monitoring was done during the first 24 hours of treatment for the second cohort., Results: For the entire patient population, the blood pressure increase [mean systolic, +10.8 mm Hg; 95% confidence interval (95% CI), 8.6-13.0; range, -5.2 to +28.7 mm Hg; mean diastolic, +8.0 mm Hg; 95% CI, 6.3-9.7; range, -4.4 to +27.1 mm Hg] was detected between days 6 and 10 (P < 0.0001 for both) and plateaued thereafter. Variability in blood pressure change did not associate with: age, body size, sex, self-reported race, baseline blood pressure, or steady-state sorafenib plasma concentrations. In the second cohort, the blood pressure elevation was detected during the first 24 hours (mean systolic, +8.2 mm Hg; 95% CI, 5.0-11.3; mean diastolic, +6.5 mm Hg; 95% CI, 4.7-8.3; P < 0.0001 for both)., Conclusions: Ambulatory blood pressure monitoring detects the blood pressure response to VEGF signaling pathway inhibition by sorafenib during the first 24 hours of treatment. The magnitude of blood pressure elevation is highly variable and unpredictable but could be important in optimizing the therapeutic index of VEGF signaling pathway inhibitor therapy.

Purpose: This was a phase I trial to determine the maximum tolerated dose and toxicity of deforolimus (AP23573, MK-8669), an inhibitor of mammalian target of rapamycin (mTOR). The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied., Experimental Design: Deforolimus was administered intravenously over 30 min every 7 days according to a flat dosing schedule. Dose was escalated according to an accelerated titration design. Patients remained on study until disease progression as long as they tolerated the drug without significant toxicities., Results: Forty-six patients were enrolled on the study. Common side effects included fatigue, anorexia, and mucositis. The maximum tolerated dose was 75 mg and mucositis was the dose-limiting toxicity. Similar to other mTOR inhibitors, deforolimus exhibited nonlinear pharmacokinetics and a prolonged half-life. Among 34 patients evaluable for response, 1 patient had a partial response, 21 patients had stable disease, and 12 had progressed. Percent change in tumor size was significantly associated with AUC (P=0.015). A significant association was also detected for maximum change in cholesterol within the first two cycles of therapy and change in tumor size (r=-0.38; P=0.029)., Conclusions: Deforolimus was well tolerated on the schedule tested in this trial with toxicity and pharmacokinetic profiles that were similar to that of other mTOR inhibitors. Additional phase II studies are needed to determine if deforolimus is superior to other mTOR inhibitors in terms of efficacy. The change in serum cholesterol as a potential biomarker of activity should be studied further.

Purpose: To investigate the safety and pharmacokinetics of R(+)XK469, a quinoxaline analogue, in patients with advanced refractory solid tumours. Preclinical studies suggested that efficacy was independent of schedule but that toxicity was decreased by dividing the dose., Methods: R(+)XK469 was initially administered as a 30 min intravenous infusion on days 1-5 of a 21-d cycle. Based on the demonstration of a long half-life, the dosing schedule was subsequently amended to infusion on days 1, 3 and 5 of a 21-d cycle. An alternate single-dose schedule of once every 21 d was also explored. Blood samples were collected for pharmacokinetic studies., Results: Dose-limiting toxicity (DLT) was neutropaenia. There was significant interindividual variability in clearance as evidenced by a coefficient of variation of 46%. A flat-dosing scheme (not based on body surface area) was justified by the absence of correlation between clearance and body surface area. A partial response was observed in a patient with nasopharyngeal carcinoma., Conclusions: The recommended phase II doses are 850-1100 mg/d on days 1, 3 and 5 of a 21-d cycle and 2500 mg on day 1 of a 21-d cycle. The observed interpatient pharmacokinetic variability should prompt investigation into the presence of genetic polymorphism in relevant metabolizing enzymes.

Tumors elicit antitumor immune responses, but over time they evolve and can escape immune control through various mechanisms, including the loss of the antigen to which the response is directed. The escape of antigen-loss variants (ALVs) is a major obstacle to T cell-based immunotherapy for cancer. However, cancers can be cured if both the number of CTLs and the expression of antigen are high enough to allow targeting of not only tumor cells, but also the tumor stroma. Here, we showed that IFN-gamma and TNF produced by CTLs were crucial for the elimination of established mouse tumors, including ALVs. In addition, both BM- and non-BM-derived stromal cells were required to express TNF receptors and IFN-gamma receptors for the elimination of ALVs. Although IFN-gamma and TNF were not required by CTLs for perforin-mediated killing of antigen-expressing tumor cells, the strong inference is that tumor antigen-specific CTLs must secrete IFN-gamma and TNF for destruction of tumor stroma. Therefore, bystander killing of ALVs may result from IFN-gamma and TNF acting on tumor stroma.

E6/E7 oncogenes of high-risk human papilloma virus (HPV) subtypes are essential for the development of certain types of cancers. However, these oncogenes are insufficient to transform normal cells into an immortalized or malignant state. Mutant Ha-ras cooperates with E6/E7 of HPV subtype 16 in transformation of cells in vitro and may contribute to some HPV-associated cancers in humans. This study investigates whether HPV16 E6/E7 and v-Ha-ras synergize in vivo. FVB/n mice transgenic for v-Ha-ras gene (R+) were crossed with transgenic C57BL/6 mice that harbor E6/E7 of HPV16 (E+). Beginning at about 3 months of age, the bitransgenic E(+)R(+)(C57BL/6 x FVB/n) F1 mice developed mouth, eye and ear tumors. By 6 months, the prevalence of these types of mouth, eye and ear tumors was 100, 71 and 79% respectively in the E(+)R+ mice. Most tumors grew progressively until the mice had to be killed. The median times for the appearance of the first mouth, eye and ear tumor were 3.6, 4.3 and 4.2 months, respectively. For the two singly transgenic groups of mice, the prevalence of mouth, eye and ear tumors was 0, 0 and 6% (E(-)R+) and 0, 0 and 0% (E(+)R-), respectively, and the median time to first tumor was greater than 12 months for singly transgenic mice (E(-)R+, E(+)R-). Thus, a remarkable synergy occurred between the v-Ha-ras and HPV16 E6/E7 oncogenes in the development of primary tumors in mice.

Therapy-related myelodysplasia and myeloid leukemia (t-MDS/t-AML) is a distinctive clinical syndrome occurring after exposure to chemotherapy (CT) or radiotherapy (RT). We report findings on 306 consecutive patients referred to our institution with morphologic review and cytogenetic analyses. Since 1972, 141 males and 165 females with a median age of 51 years (range, 3-83 years) at primary diagnosis and 58 years (range, 6-86 years) at secondary diagnosis were analyzed. Patients had been administered various cytotoxic agents, including alkylating agents (240 patients, 78%) and topoisomerase 2 inhibitors (115 patients, 39%). One hundred twenty-one (40%) had undergone CT alone, 43 (14%) had undergone RT alone, and 139 (45%) had undergone both modalities. At diagnosis of t-MDS/t-AML, 282 (92%) had clonal abnormalities involving chromosome 5 (n = 63), chromosome 7 (n = 85), chromosomes 5 and 7 (n = 66), recurring balanced rearrangements (n = 31), other clonal abnormalities (n = 39), or normal karyotype (n = 24). Abnormalities of chromosome 5, 7, or both accounted for 76% of all cases with an abnormal karyotype. Seventeen patients acquired t-MDS/t-AML after autologous stem cell transplantation, but no unique pattern of cytogenetic abnormalities was observed. Shorter latency was observed for patients with balanced rearrangements (median, 28 vs 67 months; P <.0001). Patients with acute leukemia were more likely to have balanced rearrangement than those with myelodysplasia (28% vs 4%; P <.0001). Median survival time after diagnosis of t-MDS/t-AML was 8 months; survival at 5 years was less than 10%. These data confirm and extend previous associations between clinical, morphologic, and cytogenetic findings in t-MDS/t-AML.

Purpose: O6-benzylguanine (BG) provides a means to effectively inactivate the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) and increase the chemotherapeutic effectiveness of chloroethylating and methylating agents in preclinical and clinical studies. Two different doses of BG have been reported as the optimal biochemical modulatory dose for patients (i.e., 100 and 120 mg/m2). The objective of our study was to compare these doses by measuring AGT in surgically removed specimens after treatment with BG., Experimental Design: BG was administered to patients as an i.v. infusion 16 +/- 4 h before surgical resection of their systemic tumor. AGT activity was measured in the tumor using a methylated DNA substrate. The target end point was defined as > or =11 of 13 patients with undetectable tumor AGT levels (<10 fmol/mg protein)., Results: Of the 28 patients enrolled, 25 of whom were analyzed for AGT activity, the most common primary sites of cancer included the colon (n = 11), bladder (n = 3), rectum (n = 4), and stomach (n = 3). Positive (DaOY cells) and negative (Chinese hamster ovary cells) control cell lines were included in each assay. Seven of the 12 patients treated with 100 mg/m2 BG had AGT activity of >10 fmol/mg protein (15-147 fmol/mg protein). Only 2 of the 13 patients treated with 120 mg/m2 BG had AGT activity of >10 fmol/mg protein (11 and 12 fmol/mg protein)., Conclusions: From our surgically removed tissue data, a dose of 120 mg/m2 BG is recommended to deplete systemic tumors of AGT activity.