An accurate intraoperative identification of malignant tissue is a challenge in the surgical management of breast cancer. Imaging techniques that help address this challenge could contribute to more complete and accurate tumor excision, and thereby help reduce the current high reexcision rates without resorting to the removal of excess healthy tissue. Optical coherence microelastography (OCME) is a three-dimensional, high-resolution imaging technique that is sensitive to microscale variations of the mechanical properties of tissue. As the tumor modifies the mechanical properties of breast tissue, OCME has the potential to identify, on the microscale, involved regions of fresh, unstained tissue. OCME is based on the use of optical coherence tomography (OCT) to measure tissue deformation in response to applied mechanical compression. In this feasibility study on 58 ex vivo samples from patients undergoing mastectomy or wide local excision, we demonstrate the performance of OCME as a means to visualize tissue microarchitecture in benign and malignant human breast tissues. Through a comparison with corresponding histology and OCT images, OCME is shown to enable ready visualization of features such as ducts, lobules, microcysts, blood vessels, and arterioles and to identify invasive tumor through distinctive patterns in OCME images, often with enhanced contrast compared with OCT. These results lay the foundation for future intraoperative studies. Cancer Res; 75(16); 1–10. ©2015 AACR.

Accurate intraoperative identification of malignant tissue is a challenge in the surgical management of breast cancer. Imaging techniques that help address this challenge could contribute to more complete and accurate tumor excision, and thereby help reduce the current high re-excision rates without resorting to the removal of excess healthy tissue. Optical coherence micro-elastography (OCME) is a three-dimensional, high-resolution imaging technique that is sensitive to micro-scale variations of the mechanical properties of tissue. As tumor modifies the mechanical properties of breast tissue, OCME has the potential to identify, on the micro-scale, involved regions of fresh, unstained tissue. OCME is based on the use of optical coherence tomography (OCT) to measure tissue deformation in response to applied mechanical compression. In this feasibility study on 58 ex vivo samples from patients undergoing mastectomy or wide local excision, we demonstrate the performance of OCME as a means to visualize tissue microarchitecture in benign and malignant human breast tissues. Through comparison with corresponding histology and OCT images, OCME is shown to enable ready visualization of features such as ducts, lobules, micro-cysts, blood vessels and arterioles, and to identify invasive tumor through distinctive patterns in OCME images, often with enhanced contrast compared to OCT. These results lay the foundation for future intraoperative studies.

Vaccines that can coordinately induce multi-epitope T cell–mediated immunity, T helper functions, and immunologic memory may offer effective tools for cancer immunotherapy. Here, we report the development of a new class of recombinant protein cancer vaccines that deliver different CD8+ and CD4+ T-cell epitopes presented by MHC class I and class II alleles, respectively. In these vaccines, the recombinant protein is fused with Z12, a novel cell-penetrating peptide that promotes efficient protein loading into the antigen-processing machinery of dendritic cells. Z12 elicited an integrated and multi-epitopic immune response with persistent effector T cells. Therapy with Z12-formulated vaccines prolonged survival in three robust tumor models, with the longest survival in an orthotopic model of aggressive brain cancer. Analysis of the tumor sites showed antigen-specific T-cell accumulation with favorable modulation of the balance of the immune infiltrate. Taken together, the results offered a preclinical proof of concept for the use of Z12-formulated vaccines as a versatile platform for the development of effective cancer vaccines. Cancer Res; 1–12. ©2015 AACR.

Antibody–drug conjugates (ADC) are an emerging drug class that uses antibodies to improve cytotoxic drug targeting for cancer treatment. ADCs in current clinical trials achieve a compromise between potency and physicochemical/pharmacokinetic properties by conjugating potent cytotoxins directly to an antibody at a 4:1 or less stoichiometric ratio. Herein, we report a novel, polyacetal polymer-based platform for creating ADC that use poly-1-hydroxymethylethylene hydroxymethyl-formal (PHF), also known as Fleximer. The high hydrophilicity and polyvalency properties of the Fleximer polymer can be used to produce ADC with high drug loading without compromising physicochemical and pharmacokinetic properties. Using trastuzumab and a vinca drug derivative to demonstrate the utility of this platform, a novel Fleximer-based ADC was prepared and characterized in vivo. The ADC prepared had a vinca-antibody ratio of 20:1. It exhibited a high antigen-binding affinity, an excellent pharmacokinetic profile and antigen-dependent efficacy, and tumor accumulation in multiple tumor xenograft models. Our findings illustrate the robust utility of the Fleximer platform as a highly differentiated alternative to the conjugation platforms used to create ADC currently in clinical development. Cancer Res; 75(16); 1–8. ©2015 AACR.

Antibody-drug conjugates (ADC) are an emerging drug class that utilizes antibodies to improve cytotoxic drug targeting for cancer treatment. ADC in current clinical trials achieve a compromise between potency and physicochemical/pharmacokinetic properties by conjugating potent cytotoxins directly to an antibody at a 4:1 or less stoichiometric ratio. Herein we report a novel, polyacetal polymer-based platform for creating ADC that use poly-1-hydroxymethylethylene hydroxymethyl-formal (PHF), also known as Fleximer®. The high hydrophilicity and polyvalency properties of the Fleximer polymer can be used to produce ADC with high drug-loading without compromising physicochemical and pharmacokinetic properties. Using trastuzumab and a vinca drug derivative to demonstrate the utility of this platform, a novel Fleximer-based ADC was prepared and characterized in vivo. The ADC prepared had a vinca-antibody ratio of 20:1. It exhibited a high antigen-binding affinity, an excellent pharmacokinetic profile and antigen-dependent efficacy and tumor accumulation in multiple tumor xenograft models. Our findings illustrate the robust utility of the Fleximer platform as a highly differentiated alternative to the conjugation platforms used to create ADC currently in clinical development.