Assessing the impact of the addition of dendritic cell vaccination to neoadjuvant chemotherapy in breast cancer patients: A model‐based characterization approach

Abstract

Aims: Immunotherapy is a rising alternative to traditional treatment in breast cancer (BC) patients in order to transform cold into hot immune enriched tumours and improve responses and outcome. A computational modelling approach was applied to quantify modulation effects of immunotherapy and chemotherapy response on tumour shrinkage and progression-free survival (PFS) in naïve BC patients.Methods: Eighty-three Her2-negative BC patients were recruited for neoadjuvant chemotherapy with or without immunotherapy based on dendritic cell vaccination.Sequential tumour size measurements were modelled using nonlinear mixed effects modelling and linked to PFS. Data from another set of patients (n = 111) were used to validate the model.Results: Tumour size profiles over time were linked to biomarker dynamics and PFS. The immunotherapy effect was related to tumour shrinkage (P < .05), with the shrinkage 17% (95% confidence interval: 2-23%) being higher in vaccinated patients, confirmed by the finding that pathological complete response rates in the breast were higher in the vaccinated compared to the control group (25.6% vs 13.6%; P = .04). The whole tumour shrinkage time profile was the major prognostic factor associated to PFS (P < .05), and therefore, immunotherapy influences indirectly on PFS, showing a trend in decreasing the probability of progression with increased vaccine effects.Tumour subtype was also associated with PFS (P < .05), showing that luminal A BC patients have better prognosis.Conclusions: Dendritic cell-based immunotherapy is effective in decreasing tumour size. The semi-mechanistic validated model presented allows the quantification of the immunotherapy treatment effects on tumour shrinkage and establishes the relationship between the dynamics of tumour size and PFS.

Progress and Opportunities to Advance Clinical Cancer Therapeutics Using Tumor Dynamic Models

“…* Models have most of the time been developed using clinical trial data and there is a need to develop metrics of efficacy that can be successfully applied to real-world data, such as those provided by electronic health records (79). These limitations notwithstanding, tumor dynamic modeling can be of value to assess the efficacy of new therapeutic modalities like immunotherapy-based dendritic cell vaccination for neoadjuvant chemotherapy in early breast cancer (80) or intratumoral treatments. Assessment of efficacy in terms of individual lesion size reductions is particularly important for the intratumoral administration of oncolytic viruses (81).…”

Modification of Breast Cancer Milieu with Chemotherapy Plus Dendritic Cell Vaccines: An Approach to Select Best Therapeutic Strategies

“…The control group (CG) was obtained from an historic cohort (2008-2015) treated at our center in the same way but without vaccines. Demographic features were well balanced among both groups [20]. No adjuvant chemotherapy was prescribed.…”

“…Surgical management was performed after NAC and was followed by radiation therapy ± endocrine therapy if needed. In the adjuvant setting, patients in the VG also received intradermal DCV loaded with autologous tumor lysate as described in our previous work [17,20].…”

Modification of Breast Cancer Milieu with Chemotherapy Plus Dendritic Cell Vaccines: An Approach to Select Best Therapeutic Strategies

“…All patients were treated with sequential NAC consisting of 4 cycles of dose-dense epirubicin plus cyclophosphamide with G-CSF support followed by 4 cycles of docetaxel each 21 days according to standard protocols. Patients in the experimental group also received intradermal DCV loaded with autologous tumor lysate as described in our previous work [16,17]. Surgical management was performed after NAC and was followed by radiation therapy ± hormonal therapy if needed.…”