The Cancer Immunogram as a Framework for Personalized Immunotherapy in Urothelial Cancer

Abstract

Context: The abysmal outlook of urothelial cancer (UC) has changed with the introduction of immunotherapy. Still, many patients do not respond and distinctive biomarkers are currently lacking. The rise of this novel armamentarium of immunotherapy treatments, in combination with the complex biology of an immunological tumor response, warrants the development of a comprehensive framework that can provide an overview of important immunological processes at play in individual patients.

Objective: To develop a comprehensive framework based on tumor- and host-specific parameters to understand immunotherapy response in UC. This framework can inform rational, biology-driven clinical trials and ultimately guide us toward individualized patient treatment.

Evidence acquisition: A literature review was conducted on UC immunotherapy, clinical trial data, and biomarkers of response to checkpoint inhibition.

Evidence synthesis: Here, we propose a UC immunogram, based on currently available clinical and translational data. The UC immunogram describes several tumor- and host-specific parameters that are required for successful immunotherapy treatment. These seven parameters are tumor foreignness, immune cell infiltration, absence of inhibitory checkpoints, general performance and immune status, absence of soluble inhibitors, absence of inhibitory tumor metabolism, and tumor sensitivity to immune effectors.

Conclusions: Longitudinal integration of individual patient parameters may ultimately lead to personalized and dynamic immunotherapy, to adjust to the Darwinian forces that drive tumor evolution. Incorporating multiparameter biomarkers into quantitative predictive models will be a key challenge to integrate the immunogram into daily clinical practice.

Patient summary: Here, we propose the urothelial cancer immunogram, a novel way of describing important immunological characteristics of urothelial cancer patients and their tumors. Seven characteristics determine the chance of having an immunological tumor response. Using this immunogram, we aim to better understand why some patients respond to immunotherapy and some do not, to ultimately improve anticancer therapy.

Keywords: Biomarkers; Cytotoxic T lymphocyte–associated protein 4; Immune checkpoint inhibitors; Immunotherapy; Programmed cell death 1; Programmed cell death receptor ligand 1; Urothelial cell cancer.

Fig. 1 –

Urothelial cancer immunogram. The proposed cancer immunogram for UC patients reflects seven key immunological axes and their underlying biomarkers (italic) that facilitate successful immunotherapy treatment. The immunogram is constructed on the assumption that T-cell activity is the ultimate effector mechanism that is affected by these seven unrelated axes. The outer region of the plot depicts the most favorable immune status for immunotherapy treatment. In the hypothetical patient example above, the line connects the seven parameters in a highly favorable situation for immunological antitumor response. Several examples of cancer immunograms of UC patients who were treated with anti-PD-L1 in the IMvigor210 study can be found in Figure 2 and the Supplementary material (Applications of the urothelial cancer immunogram). IDO = indolamine 2,3-dioxygenase 1; IFNg = interferon gamma; IL = interleukin; LDH = lactate dehydrogenase; NLR = neutrophil-to-lymphocyte ratio; TGF-β = transforming growth factor beta; UC = urothelial cancer; VEGF = vascular endothelial growth factor; WHO = World Health Organization.

Fig. 2 –

Example immunograms of urothelial cancer patients treated with second-line anti-PD-(L)1 checkpoint inhibition. In the UC immunograms, outer region of the plot depicts the most favorable status for a T-cell-mediated anticancer immune response, which is affected by seven unrelated axes. Immunogram scores are based on available data from individual patients on that specific axis. Orange arrow: shift of the immunogram upon anti-PD-(L)1 treatment. Immunogram axes with no available data are marked by an orange star (*) and have been qualified as favorable (hypothetically) in the immunogram. (A) A patient with a high mutational burden, favorable TCGA class II, and substantial CD8+ T-cell infiltration. The patient had favorable CD8-effector and IFNg immune activation signatures, while the PD-L1 score (IC2) was unfavorable and may have impaired natural antitumor response. The patient had a WHO performance score of 1, had no visceral metastases, and had favorable NLR ratio and LDH. All parameters, except high PD-L1 expression, were favorable for an immune response. Treatment with anti-PD-L1 corrects the only unfavorable parameter that may have prevented T cells from executing an antitumor response, and led to a complete response, which is still ongoing (OS currently 1230 d). (B) A patient with unfavorable tumor foreignness (low TMB, TCGA IV) with dramatic intratumoral CD8+ T-cell infiltration and favorable CD8-effector and IFNg immune activation signatures. The tumor environment showed high PD-L1 IC expression (PD-L1 IC2), which may have prevented T cells from eliminating tumor cells. This patient had WHO 1 with no visceral metastases and favorable NLR ratio and LDH. While this patient had dramatic intratumoral CD8+ T-cell infiltration with a favorable immune gene signature, treatment with anti-PD-L1 did not result in a tumor response and OS (117 d) was limited. In this case, involvement of other inhibitory checkpoint pathways, regulatory T cells, or presence of soluble inhibitors (ie, TGF-β) may explain anti-PD-L1 resistance. Furthermore, despite having sufficient CD8+ T-cell infiltration, a limited tumor-specific T-cell repertoire may explain nonresponse despite having sufficient CD8+ T-cell infiltration. Treatment with anti-PD-(L)1/CTLA-4 might hypothetically have resulted in a broader and more effective immune response. More examples can be found in the Supplementary material (Applications of the urothelial cancer immunogram). IC = immune cell; IDO = indolamine 2,3-dioxygenase 1; IFNg = interferon gamma; IL = interleukin; LDH = lactate dehydrogenase; NLR = neutrophil-to-lymphocyte ratio; OS = overall survival; TCGA = The Cancer Genome Atlas; TGF-β = transforming growth factor beta; TMB = tumor mutational burden; UC = urothelial cancer; VEGF = vascular endothelial growth factor; WHO = World Health Organization.