Cabo is an emerging tyrosine kinase inhibitor in mRCC but its impact on systemic tumor immunity is unknown. We investigated the activity of Cabo in modulating blood innate and adaptive immunity in mRCC pts.
15 mRCC pts receiving Cabo (60 mg per os/daily) as per clinical practice were prospectively analyzed at baseline and 3 months for blood immune profiling by 13-color cytofluorimetry on peripheral blood mononuclear cell (PBMC). Pts had clear (n = 12) or non-clear cells (n = 4) histology, with intermediate (n = 7), poor (n = 8) and good (n = 1) risk according to Heng prognostic score, and received at least 2 (n = 9), 1 (n = 2) or none (n = 5) previous therapies, including Nivolumab (n = 4).
A significant reduction of myeloid immunosuppressive cell subsets in favor of protective antitumor adaptive and innate immunity was detected in most post vs pre PBMC. Specifically, granulocytic myeloid-derived suppressor cells (MDSC) (CD11b+CD15+HLA-DRneg), monocytic MDSC (CD11b+CD14+HLA-DRneg) and TIM3+ myeloid cells (CD15+TIM3+ and CD14+TIM3+) were remarkably reduced. Total CD11b+CD14+ cells were also decreased, while classical protective (CD14+CD16-HLA-DRhigh) and patrolling (CD14+CD16dimCX3CR1+) monocytes showed a clear boost. Concomitantly, higher frequency of cytolytic and activated NK cells (CD3-CD16+CD56dim vs CD3-CD56+CD16+PD-1+, respectively), paralleled by a decrease of anergic NK cells (CD3+CD16+CD56+TIM3+), was detected in post-Cabo samples. Activated CD8+ and CD4+ T cells (CD3+CD8/CD4+ CD69+ cells) were also raised by treatment along with a specific increase of ADCC-prone CD3+CD16dimCD56- T cells. These latter data indicate that Cabo could intensify direct and Ab-mediated enhancing tumor killing potential in NK and T cells, either as direct effect or through the reduced immunosuppressive pressure exerted by myeloid populations.
Cabo mediates a rapid remodeling of myeloid cells from an immunosuppressive to an antitumor phenotype, with a priming of circulating cytotoxic NK and T cells. Even in advanced disease, Cabo can still contribute to reset systemic immune conditions by creating more favorable conditions for immunotherapy.
Clinical trial identification
Legal entity responsible for the study
Fondazione IRCCS Istituto Nazionale Tumori of Milan.
Has not received any funding.
E. Verzoni: Honoraria: Ipsen, Novartis, Pfizer. G. Procopio: Honoraria: BMS, Ipsen, Novartis, Pfizer. All other authors have declared no conflicts of interest.