Introduction: Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in breast cancer cell lines. Combination of everolimus also known as RAD001 (oral mammalian target of rapamycin (mTOR) inhibitor) and carboplatin may have activity in metastatic triple-negative breast cancer (TNBC). Methods: The primary objective of this study was to determine clinical benefit rate (CBR), that is (complete remission (CR) + partial remission (PR) + stable disease (SD) lasting ≥6 months) and the toxicity of everolimus/carboplatin in women with metastatic TNBC. Prior carboplatin was allowed. Treatment consisted of intravenous carboplatin area under the curve (AUC) 6 (later decreased to AUC 5 and subsequently to AUC 4) every 3 weeks with daily 5 mg everolimus. Results: We enrolled 25 patients in this study. Median age was 58 years. There were one CR, six PRs, seven SDs and eight PDs (progression of disease). CBR was 36% (95% confidence interval (CI) 21.1 to 57.4%). One SD was achieved in a patient progressing on single agent carboplatin. The median progression free survival (PFS) was 3 months (95% CI 1.6 to 4.6 months) and overall survival (OS) was 16.6 months (95% CI 7.3 months to not reached). There were seven patients (28%) with ≥ grade 3 thrombocytopenia; three (12%) with grade 3 neutropenia (no bleeding/febrile neutropenia) and one (4%) with grade 3 anemia. Greater hematological toxicity was seen in the first seven patients treated with carboplatin AUC5/6. After the amendment for starting dose of carboplatin to AUC 4, the regimen was well tolerated with only one out of 18 patients with grade 3 neutropenia and two patients with grade 3 thrombocytopenia. There was only one case of mucositis. Conclusion: Everolimus-carboplatin was efficacious in metastatic TNBC. Dose limiting hematological toxicity was observed when AUC5/6 of carboplatin was combined with everolimus. However, carboplatin AUC 4 was well tolerated in combination with everolimus with continuing responses. Trial registrations: ClinicalTrials.gov NCT01127763.

Zimmerman BS, et al. J Breast Cancer. 2020 Oct;23(5):542-552. https://doi.org/10.4048/jbc.2020.23.e56

Immunotherapies like immune checkpoint inhibitors (ICI) have changed the standard of care for patients with cancer, often leading to durable responses. However, many patients remain or become refractory to ICIs owing to factors such as a lack of primed neoantigen-reactive T cells. We developed a peptide-based vaccination platform that utilizes fully personalized genome vaccines (PGV) and targets neoantigens predicted by our OpenVax computational pipeline. In this study, we report results from the PGV001 study (NCT02721043) targeting up to 10 neoantigens, administered in the adjuvant setting to patients with both solid and hematologic malignancies who have high risk of recurrence. Our data indicate that PGV001 is feasible and safe, with 13 of 14 enrolled patients receiving the vaccine and 11 completing the treatment. 100% of vaccinated patients developed targeted T-cell and B-cell responses, highlighting the capacity of OpenVax to predict immunogenic neoantigens and the potential of PGV001 for safely inducing targeted immunity. Significance: The PGV001 platform is feasible, safe, and immunogenic. The OpenVax pipeline predicted immunogenic neoantigens in tumors with wide-ranging mutational burdens. Data from this study prompted three additional PGV001 trials, one in newly diagnosed glioblastoma, one in urothelial cancer in combination with an ICI, and another in prostate cancer.

To evaluate the safety of administering fluorouracil (5FU)-based chemotherapy to cancer patients with inflammatory bowel disease (IBD). We retrospectively reviewed all patients entered into the Memorial Sloan-Kettering Cancer Center clinical data base from 1985 through 1995 who had a diagnosis of IBD, had a gastrointestinal malignancy, and were treated with systemic 5FU-based chemotherapy. A total of 19 patient charts were identified and reviewed. Fifty-three percent of patients reviewed experienced severe (grade III/IV) diarrhea on treatment. Sixty percent of patients with a history of active IBD and 40% of patients with a history of inactive IBD experienced severe diarrhea on treatment. The incidence of severe diarrhea did not appear to be substantially influenced by age, schedule of 5FU administration, concurrent radiation, or type of IBD. While there does appear to be an increased risk of diarrhea exacerbation in IBD patients treated with 5FU, a substantial number of patients tolerate chemotherapy without increased difficulty. The degree of IBD activity or other clinical parameters can not be used to predict accurately the likelihood of toxicity.

Breast cancer is the most commonly diagnosed non-cutaneous cancer and is the leading cause of cancer mortality in females worldwide. Breast cancer incidence has been increasing over the last few decades; simultaneously, novel therapeutic agents including immunotherapies and targeted therapies have become more prominent in use. Radiation therapy continues to serve as a cornerstone to breast cancer treatment in both early-stage and locoregionally advanced disease. Given the improvement in systemic agents, there is increasing interest in investigating the potential synergistic effect of radiation therapy and immunotherapy. As new trials and studies emerge demonstrating the clinical benefits of immune checkpoint inhibitors (ICIs) in breast cancer, especially in PD-L1-positive triple-negative breast cancer (TNBC), it is crucial to investigate the safety and efficacy of combining immunotherapy with radiation treatment. This narrative review discusses the impact of radiation therapy on anti-tumor immunogenicity, and examines the role of immunotherapy and radiation therapy in early-stage, locally advanced, recurrent, and metastatic breast cancer. We conducted a targeted literature search between 2010 and 2024, and included phase II/III clinical trials, mechanistic studies, and ongoing trials that evaluated the combination of immunotherapy (IO) and radiation therapy (RT). We discuss ongoing clinical studies, side effects, and optimal timing of combined IO and RT to enhance therapeutic outcomes.