Abstract PL02-03: Combination with/of immunotherapies
Authors: Blank Christian 
Published: May 2016

Systemic treatment of melanoma has faced a revolution the last decade. After 30 years of disappointments and no clinical benefit for patients, targeted agents, like the BRAF inhibitors vemurafenib or dabrafenib, and checkpoint inhibitors of CTLA-4 or PD-1/PD-L1, like ipilimumab, pembrolizumab or nivolumab, have improved for the first time the overall survival of late stage melanoma patients in phase 3 trials. Addition of MEK inhibitors to the BRAF inhibitors and combination of CTLA-4 and PD-1 blockade were able to improve the response rate and progression free survival further.

However, despite these promising data, a considerable percentage of patients will not benefit long-term from these treatments.

This raises questions in two directions: 1) how can we identify the patients that benefit long-term from current treatment options, and 2) what are future therapies, that should be tested in patients that do not benefit from current standards.

Based on recent analyses from mainly expanded access programs and safety trials we propose to characterize patients (‘ tumors) according to:

a) Tumor foreignness, e.g. mutational load,

b) General immune status, e.g. lymphocyte count,

c) Infiltration capacity, e.g. intratumoral CD8 infiltration,

d) Absence of locally expressed inhibitory factors, e.g. PD-L1,

e) Absence of local soluble inhibitory factors, e.g. IL-6, as measured by surrogate markers like C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR),

f) Absence of inhibitory tumor metabolism, e.g. as measured by LDH or glucose uptake, and

g) Sensitivity to effector mechanisms, like MHC expression.

Most these markers have already been identified to be clinical relevant for the patient's outcome upon T cell checkpoint blockade, and been shown to be crucial mechanisms for anti-tumor immune response in preclinical models. They often have a prognostic and a predictive relevance for patients treated with checkpoint modulators. This often raised critic cannot be solved, particularly for immune modulatory therapies, as the immune system, as effector compartment of any of these therapies is upfront any intervention present in the cancer patients, and thus will have always also prognostic relevance. Nevertheless, these clinical markers are important tools to understand requirements for an effective anti-tumor immune response in any cancer, and can be used to develop a cancer immunogram for individual patients or malignancies.

Based on this immunogram personalized immunotherapy can be applied using current/future combinations of immunotherapeutic approaches and agents used in targeted therapy. I will discuss several of such combination therapy options currently tested in early phase trials that address the different levels of the cancer immunogram.

Citation Format: Christian Blank. Combination with/of immunotherapies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL02-03.