4560 - Cell Phenotypes Associated with Response and Toxicity Defined by High Resolution Flow Cytometry in Melanoma Patients receiving Checkpoint Inhibition

Background

Peripheral blood T cell and myeloid-derived suppressor cells (MDSC), as well as myeloid and macrophage subsets, have been associated with a poor clinical outcome in a variety of cancers. We analyzed circulating cells from patients (pts) that received either nivolumab (NIVO) then ipilimumab (IPI) (cohort A, 16 pts) or IPI then NIVO (cohort B, 17 pts) in a randomized clinical trial to determine if peripheral blood phenotypes were associated either at baseline or on treatment with outcome.

Methods

Frozen peripheral blood mononuclear cells (PBMC) from the ChekMate 064 study were assessed at baseline and on treatment at week 13 for circulating cell subsets by 28-color, high-dimensional flow cytometry with CytoBrute, a rapid computational platform that performs high-parameter Boolean analysis. Correlations with response and survival as well as toxicity were evaluated using the machine learning algorithm ElasticNet.

Results

In cohort B pts the frequency of resting Ki67-, long-lived memory CD45+/CD45RO+/CD127+ T cells was reduced (p = 0.005), and dividing Ki-67+ CD4+/CD45RO+/CD95+ T cells susceptible to apoptosis were increased after IPI (p = 0.007), but were associated at baseline with a poor outcome with cohort A (p = 0.0002). Subsets of myeloid cells that were CD66b+/CD33+/41-BB+/CD86+ at baseline were associated with survival in cohort B (p = 0.0006). A macrophage subset that was PD-L2+/CD163+/41-BBL+/CD40+ was associated with survival for cohort A (p = 0.0001). Additional phenotypes were associated with grade 1 compared with grades 2-4 toxicity that differentiated side effects from either IPI or NIVO, and other phenotypes distinguished normals and pts (AUC=0.96).

Conclusions

A circulating CD4+/CD45RO+/CD95+ proliferating memory T cell phenotype signature is augmented after IPI and is associated at baseline with poor survival with NIVO in CheckMate 064. We discriminated pts and healthy controls with great specificity and sensitivity at baseline, and demonstrated new phenotypes associated with immune-related toxicity. Peripheral blood immune monitoring may be of value in selecting melanoma pts to be treated with immunotherapy.

Clinical trial identification

NCT01783938.

Editorial acknowledgement

Legal entity responsible for the study

BMS.

Funding

Perlmutter Cancer Center.

Disclosure

J.S. Weber: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Genentech; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy: EMD Serono; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Hoffmann-La Roche. S. Hodi: Honoraria (self), Advisory / Consultancy: BMS. M. Wind-Rotolo: Full / Part-time employment: BMS. D. Woods: Shareholder / Stockholder / Stock options: BMS. All other authors have declared no conflicts of interest.