David E. Weng

A phase I clinical trial of a ribozyme-based angiogenesis inhibitor targeting vascular endothelial growth factor receptor-1 for patients with refractory solid tumors

Purpose: This study intended to determine the maximum tolerated dose, safety, pharmacokinetic variables, clinical response, and pharmacodynamic markers of daily s.c. administration of Angiozyme. Patients and Methods: Patients with refractory solid tumors were enrolled in a dose escalation and expanded cohort design. Dose escalation involved cohorts of patients at doses of 10, 30, 100, or 300 mg/m2/d for 29 days. A second component enrolled 15 additional patients at a daily dose of 100 mg/m2. Patients were eligible to continue on therapy until disease progression. Results: Thirty-one patients were enrolled and 28 were evaluable (range, 29–505 days; median, 89.5 days). A maximum tolerated dose was not defined by toxicity but rather by the maximal deliverable dose of 300 mg/m2/d. Grade 1 to 2 injection site reactions were the most common toxicities. One patient in the 300 mg/m2 group experienced a reversible grade 3 injection site reaction. Angiozyme showed dose-dependent plasma concentrations with good bioavailability. Surrogate markers showed Angiozyme localization in tumor biopsies and a significant increase in serum von Willebrand factor antigen, a marker for endothelial cell dysfunction. Although Angiozyme-reactive antibody production was noted for some patients, no antibody-related adverse events were noted. Seven of 28 (25%) evaluable patients had stable disease for ≥6 months, with the longest treatment duration of ≥16 months. Two patients (nasopharyngeal carcinoma and melanoma) showed minor responses. Conclusion: Angiozyme was well tolerated with satisfactory pharmacokinetic variables for daily s.c. dosing. Results have provided the basis for subsequent clinical trials of this first-of-class biologically targeted therapeutic.

Antitumor efficacy of IPI-504, a selective heat shock protein 90 inhibitor against human epidermal growth factor receptor 2–positive human xenograft models as a single agent and in combination with trastuzumab or lapatinib

IPI-504 is a novel, highly soluble small-molecule inhibitor of heat shock protein 90 (Hsp90), a protein chaperone essential for regulating homeostasis of oncoproteins and cell signaling proteins. Human epidermal growth factor receptor 2 (HER2; ErbB2) oncoprotein, expressed in a subset of metastatic breast cancers, is a Hsp90 client protein. In this study, we investigated the antitumor activity and the mechanism of action of IPI-504 in HER2+, trastuzumab-sensitive and trastuzumab-refractory cell lines in vitro and in vivo. IPI-504 exhibited potent antiproliferative activities (range of IC50, 10-40 nmol/L) against several tumor cell lines examined, whereby mechanism of action was mediated through HER2 and Akt degradation. Both intravenous and oral administration of IPI-504 assessed in multiple schedules showed potent tumor growth inhibition in vivo with corresponding degradation of HER2. The tolerability and efficacy of IPI-504 combined with either trastuzumab or lapatinib were also investigated in HER2+ tumor xenograft models. Combination of IPI-504 with trastuzumab significantly enhanced tumor growth delay and induced greater responses when compared with either agent alone. Although, as expected, trastuzumab alone did not exhibit any significant antitumor activity in the trastuzumab-resistant JIMT-1 model, IPI-504 administered in combination with trastuzumab yielded greater antitumor efficacy than either agent alone. Finally, combination of IPI-504 and lapatinib was well tolerated up to 50 mg/kg IPI-504 and 100 mg/kg lapatinib and resulted in significant delay in tumor growth, including partial and complete tumor responses. These lines of evidence support the development of IPI-504 in HER2-positive breast cancers as a single agent and in combination with either trastuzumab or lapatinib.[Mol Cancer Ther 2009;8(8):2131–41]

Helper-independent, L-selectin(low) CD8+ T cells with broad anti-tumor efficacy are naturally sensitized during tumor progression

We recently reported that the CD4+ T cell subset with low L-selectin expression (CD62Llow) in tumor-draining lymph nodes (TDLN) can be culture activated and adoptively transferred to eradicate established pulmonary and intracranial tumors in syngeneic mice, even without coadministration of IL-2. We have extended these studies to characterize the small subset of L-selectinlow CD8+ T cells naturally present in TDLN of mice bearing weakly immunogenic tumors. Isolated L-selectinlow CD8+ T cells displayed the functional phenotype of helper-independent T cells, and when adoptively transferred could consistently eradicate, like L-selectinlow CD4+ T cells, both established pulmonary and intracranial tumors without coadministration of exogenous IL-2. Whereas adoptively transferred L-selectinlow CD4+ T cells were more potent on a cell number basis for eradicating 3-day intracranial and s.c. tumors, L-selectinlow CD8+ T cells were more potent against advanced (10-day) pulmonary metastases. Although the presence of CD4+ T cells enhanced generation of L-selectinlow CD8+ effector T cells, the latter could also be obtained from CD4 knockout mice or normal mice in vivo depleted of CD4+ T cells before tumor sensitization. Culture-activated L-selectinlow CD8+ T cells did not lyse relevant tumor targets in vitro, but secreted IFN-γ and GM-CSF when specifically stimulated with relevant tumor preparations. These data indicate that even without specific vaccine maneuvers, progressive tumor growth leads to independent sensitization of both CD4+ and CD8+ anti-tumor T cells in TDLN, phenotypically L-selectinlow at the time of harvest, each of which requires only culture activation to unmask highly potent stand-alone effector function.

A Phase I Study of the SMAC-Mimetic Birinapant in Adults with Refractory Solid Tumors or Lymphoma

The inhibitor of apoptosis (IAP) family of antiapoptotic proteins has been identified as a target for small molecule inhibitors in cancer. Second mitochondrial-derived activator of caspases (SMAC) efficiently and naturally antagonizes IAPs, and preclinical studies have determined that SMAC mimetics have potent anticancer properties. Here, we report a first-in-human trial designed to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics/pharmacodynamics (PK/PD) of birinapant, a novel SMAC mimetic. Patients with advanced solid tumors or lymphoma were enrolled in a 3+3 dose escalation design with birinapant administered intravenously from 0.18 to 63 mg/m2 once weekly every 3 of 4 weeks. Fifty patients were enrolled to 12 dose cohorts. Birinapant 47 mg/m2 was determined to be the MTD. At 63 mg/m2, dose-limiting toxicities included headache, nausea, and vomiting. Two cases of Bells palsy (grade 2) also occurred at 63 mg/m2. Birinapant had a plasma half-life of 30 to 35 hours and accumulated in tumor tissue. Birinapant suppressed cIAP1 and increased apoptosis in peripheral blood mononuclear cells and tumor tissue. Prolonged stable disease was observed in 3 patients: non–small cell lung cancer (5 months), colorectal cancer (5 months), and liposarcoma (9 months). Two patients with colorectal cancer had radiographic evidence of tumor shrinkage. In conclusion, birinapant was well tolerated with an MTD of 47 mg/m2 and exhibited favorable PK and PD properties. Several patients demonstrated stable disease and evidence of antitumor activity. These results support the ongoing clinical trials of birinapant in patients with cancer. Mol Cancer Ther; 14(11); 2569–75. ©2015 AACR.

The 2003 revised TNM staging system for breast cancer: results of stage re-classification on survival and future comparisons among stage groups.

BackgroundChanges to TNM staging criteria for breast cancer, introduced in 2003, have resulted in stage re-classification for some tumors. The most frequently implemented change has resulted in tumors associated with more than three positive axillary nodes being upstaged.We hypothesize these TNM staging changes would result in more TNM Stage IIB, IIIA, and IIIB tumors and that disease-specific survival estimates would change under the new staging system.MethodsA review of data was completed for patients diagnosed with breast cancer between 1 January 1995 and 31 December 2000. Tumors that would have been staged differently under the 2003 system were identified and re-classified.Clinical outcomes were determined and disease-specific survival estimates were compared relative to TNM Stage using the old and new staging systems.Data were analyzed using the log-rank test and the method of Kaplan and Meier was used to generate survival curves.ResultsData were available for 2492 tumors, of which 919 were candidates for re-classification, including 829 old Stage II, 59 old Stage III, and 31 old Stage IV. Of these 919, 159 (17%) underwent stage re-classification using the new system. Separate survival estimates for patients who had been under old stage IIA/B, IIIA/B were generated; patients upstaged from IIA or IIB demonstrated a significant difference in survival.ConclusionsStage specific survival curves indicated decreased survival for patients whose tumors had been upstaged from IIA or IIB under the old system; survival for all other patients remained unchanged.

Prognostic significance of residual breast disease and axillary node involvement for patients who had primary induction chemotherapy for advanced breast cancer

BackgroundWe performed this study to determine the prognostic significance of clinical tumor size, pathologic measurement of residual tumor, and number of positive axillary nodes in the surgical specimen relative to overall survival for patients who underwent primary induction chemotherapy for advanced breast cancer.MethodsData, collected prospectively between 1997 and 2002, included clinical tumor-node-metastasis stage, age at diagnosis, hormone receptor status, type of preoperative chemotherapy, histological type, surgical procedure, pathologic measurement in centimeters of residual breast tumor, and the number of positive axillary nodes in the surgical specimen. Univariable correlates of residual breast disease were assessed by using the χ2 test. Recursive partitioning analysis was used to determine the prognostic significance of clinical tumor size, residual tumor size, and pathologic node involvement relative to overall survival. Survival was estimated by using the method of Kaplan and Meier and compared by using the log-rank test. A P value of < .05 was considered significant.ResultsData were available for 85 patients with advanced breast cancer. Although univariable analysis identified increasing age, clinically involved axillary nodes, and a higher clinical tumor-node-metastasis stage as predictors of an increased risk of residual disease, recursive partitioning analysis identified more than three involved axillary nodes in the surgical specimen, with or without any measurable residual breast disease, as the most significant predictor of decreased survival (P < .001).ConclusionsPathologic axillary node involvement was the most significant predictor of decreased survival for patients who had undergone primary induction chemotherapy for advanced breast cancer.

T-Cell Adoptive Immunotherapy

Adoptive transfer originally referred to the ability to confer protective immunity on a naive host via infusion of T lymphocytes from an immune donor. This term now also encompasses a strategy of cancer therapy in which autologous T cells are acquired from a tumor-bearing host then activated and numerically expanded ex vivo prior to reinfusion. It has been nearly 50 yr since Mitchison’ s initial observation that adoptive transfer of “cellular elements” from immune hosts could accelerate rejection of tumor transplants in naive recipients (1). Since then, considerable progress has been made in defining T lymphocytes as the central component of the antitumor response with the ability to directly kill tumor cells and orchestrate other host effector mechanisms. With the importance of T cells firmly established, tumor-reactive T-cell clones have been successfully used as probes to identify tumor-associated antigens that are currently being investigated as vaccine reagents.