Combined Tumor Cell-Based Vaccination and Interleukin-12 Gene Therapy Polarizes the Tumor Microenvironment in Mice

Tumor progression depends on tumor milieu, which influences neovasculature formation and immunosuppression. Combining immunotherapy with antiangiogenic/antivascular therapy might be an effective therapeutic approach. The aim of our study was to elaborate an anticancer therapeutic strategy based on the induction of immune response which leads to polarization of tumor milieu. To achieve this, we developed a tumor cell-based vaccine. CAMEL peptide was used as a B16-F10 cell death-inducing agent. The lysates were used as a vaccine to immunize mice bearing B16-F10 melanoma tumors. To further improve the therapeutic effect of the vaccine, we combined it with interleukin (IL)-12 gene therapy. IL-12, a cytokine with antiangiogenic properties, activates nonspecific and specific immune responses. We observed that combined therapy is significantly more effective (as compared with monotherapies) in inhibiting tumor growth. Furthermore, the tested combination polarizes the tumor microenvironment, which results in a switch from a proangiogenic/immunosuppressive to an antiangiogenic/immunostimulatory one. The switch manifests itself as a decreased number of tumor blood vessels, increased levels of tumor-infiltrating CD4+, CD8+ and NK cells, as well as lower level of suppressor lymphocytes (Treg). Our results suggest that polarizing tumor milieu by such combined therapy does inhibit tumor growth and seems to be a promising therapeutic strategy

Abstract P3-12-01: Locoregional failure rates do not vary by breast cancer subtype after mastectomy in a modern cohort of patients with T1-2 tumors with 1-3 pathologically involved lymph nodes

Abstract Purpose/Objective(s): A recent meta-analysis of 22 randomized trials accrued between 1964-86 demonstrated significantly higher rates of locoregional failure (LRF), total failure (TF) and breast-cancer mortality in women with 1-3 positive (+) axillary lymph nodes (ALN) who did not receive radiotherapy after mastectomy (mast.). Given the improvements in diagnostic and therapeutic approaches, the challenge today is whether breast cancer patients with T1-T2 tumors with 1-3+ ALN have similar substantial risk that routinely warrants the delivery of post mastectomy radiotherapy (PMRT). We further set out to explore whether the risk of failure varies by breast cancer subtype. Materials/Methods: We reviewed patients with pathologic T1-2N1 breast cancer treated with initial mast. and adjuvant systemic therapy (ST) from 2000-2013. The primary endpoint was LRF, defined as a recurrence in either the ipsilateral chestwall or regional lympatics (axillary, internal mammary, or supraclavicular nodes). Secondary endpoints include rates of TF (LRF or distant metastases), disease-free survival (DFS, failure or death), and overall survival (OS). Patients were classified into 3 basic subtypes: hormone receptor positive/HER2 negative (HR+), HER2 positive (HER2+), and triple negative (TN). Survival analysis was performed using the Kaplan-Meier method. The log-rank test was used to compare survival between groups. Results: We identified 550 eligible patients from our prospectively maintained cancer registry. Median follow-up was 5 years. Baseline characteristics included median age 53 yrs, 61% pathologic T2, 39% grade 3, 48% with lymphovascular invasion. Subtypes included 72% HR+ (n=393), 16% HER2+ (n=89), 12% TN (n=66) and 0.4% unknown (n=2). Treatment included chemotherapy in 78% (n=428), PMRT in 15% (n=82), and anti-endocrine therapy in 70% (n=385). A median of 18 ALN (range, 1-68) were removed, 10% (N=55) had sentinel-lymph node biopsy only, and 17%(N=95) had micrometastases (N1mic) only. A total of 296 pts had 1+ node, 165 pts 2+ nodes and 89 pts 3+ nodes. The 5 yr LRF rate for the entire cohort was 3.9% and patients with 1+, 2+, and 3+ nodes had 5 yr LRF of 2.6%, 4.7% and 6.4%, respectively (p=0.79). The 5 yr LRF for HR+, HER2+ and TN was 3.9%, 1.5%, and 6.6%, respectively (p=0.39). When stratified by 1+, 2+ or 3+ nodes, the 5 yr LRF for HR+ vs. HER2+ vs. TN were 2.4%, 6.8%, and 0% vs. 5.8%, 15.4%, and 0% vs. 5.7%, 0%, and 4.8%, p=0.43. The 5 yr TF, DFS, and OS rates for HR+, HER2+ and TN were 90.5% vs. 88.5%. vs. 83.6% (p=0.76); 84.9% vs. 82.6% vs. 79.2% (p=0.85); and 91.4% vs. 86.2% vs. 81.3% (p=0.83). Conclusions: In a cohort of patients with T1-2N1 breast cancer treated with modern therapy, we found low rates of LRF which did not vary amongst HR+, HER2+ and TN patients. In particular, HR+ patients with 1+ LN had extremely low rates of LRF Given these low recurrence rates, caution should be given in routinely recommending PMRT for every woman with 1-3+ ALN after mast. and adjuvant ST. Citation Format: Bazan JG, Majithia L, Quick AM, Terando AM, Agnese D, Mrozek E, Farrar W, White JR. Locoregional failure rates do not vary by breast cancer subtype after mastectomy in a modern cohort of patients with T1-2 tumors with 1-3 pathologically involved lymph nodes. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-12-01.</jats:p