Rationalizing the pathway to personalized neoadjuvant immunotherapy: the Lombard Street Approach

Abstract

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.

Patient-Derived Explants as a Precision Medicine Patient-Proximal Testing Platform Informing Cancer Management

“…Interestingly, anti-PD-1 (nivolumab) treatment of PD-L1 + melanoma PDEs increased the inter-cell distance between T cell subsets, demonstrating mechanisms whereby CTLs may avoid Treg-mediated immunosuppression in the TME following immunotherapy ( 67 ). As the numbers of studies incorporating PDEs with immunotherapy grows, future pipelines could be assessed in parallel with multiple mRNA and protein readouts to assess immunological response in patients eligible for anti-PD-1, anti-PD-L1 or anti-CTLA-4 treatment, as described in the Lombard Street Approach ( 68 ).…”

Integrated functional and spatial profiling of tumour immune responses induced by immunotherapy: the iPROFILER platform

“…Moreover, such platforms can allow the identification of non-responding patients as well as potential underlying causes of resistance, which could facilitate the development of novel treatments, as suggested recently in the context of neoadjuvant immunotherapy combination trials in melanoma. 19 This study reports a model system that, by preserving the cellular diversity and spatial interactions between tumour, stromal and immune populations, enables the dissection of in-situ immune responses after immunotherapeutic perturbations. As this was a proof-of-concept study, it is noted that the iPROFILER platform in its current form still has some limitations that may be optimized in future studies.…”

“…Hence, technologies that can profile both the composition and architecture of the TME, as well as broad changes in immune activity upon treatment are crucial to gain a deeper understanding of how such immune responses develop. 17 - 19 This study describes the iPROFILER platform, which, by integrating multidimensional readouts in a flexible and modular manner, allows combined assessment of dynamic and spatial properties of treatment-induced immune responses in human cancer samples.…”

“…Moreover, such platforms can allow the identification of non-responding patients as well as potential underlying causes of resistance, which could facilitate the development of novel treatments, as suggested recently in the context of neoadjuvant immunotherapy combination trials in melanoma. 19 …”

Adjuvant versus Neoadjuvant Immunotherapy for Hepatocellular Carcinoma: Clinical and Immunologic Perspectives

“…[65][66][67] Therefore, neoadjuvant ICI-based therapy may serve as a platform for the development of new treatment combinations using small proof-of-concept clinical trials. 68 Comparisons of the theoretical basis and issues of clinical trial design between adjuvant and neoadjuvant therapy are summarized in ►Table 1. While most of the scientific rationales of trial design and experience in clinical trials were derived from melanoma studies, these rationale and experience may be applicable in other cancer types including HCC.…”