Neoadjuvant chemo(radio)
therapy is part of the established standard of care in
cancer treatment; neoadjuvant application of
immunotherapy, however, is only performed within recent trials. Combination of
programmed cell death protein 1 and
cytotoxic T lymphocyte antigen 4 blockade shows promising results with high pathologic response rates in the neoadjuvant setting and a very low relapse rate in the responding patients. In addition, neoadjuvant administration allows direct determination of treatment efficacy within the individual patient, and offers easy access to paired
tumor material, both pretherapy and post-
therapy, thus facilitates the rational development of new combinations driven by preclinical analyses. Patient-derived human
tumor explant systems such as a recently developed human patient-derived
tumor fragment platform can provide an additional tool to further rationalize the development of new treatment combinations. We will discuss neoadjuvant
immunotherapy as a unique opportunity for rational trial design, the development of immune signatures for non-responding patients to steer clinical trial development, and the use of patient-derived ex vivo models to identify new personalized
immunotherapy combinations. In this context, we propose the 'Lombard Street Approach', a back and forth approach of characterizing non-responders on neoadjuvant
immunotherapy combinations, identifying promising new combinations for this group in the
tumor fragment platform, and performing subsequently signature-driven small proof-of-concept combination trials. Repeating this approach with smaller and smaller groups of non-responders will step by step increase the percentage of patients benefiting from neoadjuvant
immunotherapy in a rational and fast manner.