Palbociclib impairs the proliferative capacity of activated T cells while retaining their cytotoxic efficacy.

The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib is an emerging cancer therapeutic that just recently gained Food and Drug Administration approval for treatment of estrogen receptor (ER)-positive, human epidermal growth factor receptor (Her)2-negative breast cancer in combination with the ER degrader fulvestrant. However, CDK4/6 inhibitors are not cancer-specific and may affect also other proliferating cells. Given the importance of T cells in antitumor defense, we studied the influence of palbociclib/fulvestrant on human CD3+ T cells and novel emerging T cell-based cancer immunotherapies. Palbociclib considerably inhibited the proliferation of activated T cells by mediating G0/G1 cell cycle arrest. However, after stopping the drug supply this suppression was fully reversible. In light of combination approaches, we further investigated the effect of palbociclib/fulvestrant on T cell-based immunotherapies by using a CD3-PSCA bispecific antibody or universal chimeric antigen receptor (UniCAR) T cells. Thereby, we observed that palbociclib clearly impaired T cell expansion. This effect resulted in a lower total concentration of interferon-γ and tumor necrosis factor, while palbociclib did not inhibit the average cytokine release per cell. In addition, the cytotoxic potential of the redirected T cells was unaffected by palbociclib and fulvestrant. Overall, these novel findings may have implications for the design of treatment modalities combining CDK4/6 inhibition and T cell-based cancer immunotherapeutic strategies.

Targeting Acute Myeloid Leukemia Using the RevCAR Platform: A Programmable, Switchable and Combinatorial Strategy.

Clinical translation of novel immunotherapeutic strategies such as chimeric antigen receptor (CAR) T-cells in acute myeloid leukemia (AML) is still at an early stage. Major challenges include immune escape and disease relapse demanding for further improvements in CAR design. To overcome such hurdles, we have invented the switchable, flexible and programmable adaptor Reverse (Rev) CAR platform. This consists of T-cells engineered with RevCARs that are primarily inactive as they express an extracellular short peptide epitope incapable of recognizing surface antigens. RevCAR T-cells can be redirected to tumor antigens and controlled by bispecific antibodies cross-linking RevCAR T- and tumor cells resulting in tumor lysis. Remarkably, the RevCAR platform enables combinatorial tumor targeting following Boolean logic gates. We herein show for the first time the applicability of the RevCAR platform to target myeloid malignancies like AML. Applying in vitro and in vivo models, we have proven that AML cell lines as well as patient-derived AML blasts were efficiently killed by redirected RevCAR T-cells targeting CD33 and CD123 in a flexible manner. Furthermore, by targeting both antigens, a Boolean AND gate logic targeting could be achieved using the RevCAR platform. These accomplishments pave the way towards an improved and personalized immunotherapy for AML patients.

The Evolving Landscape of Biomarkers for Anti-PD-1 or Anti-PD-L1 Therapy.

The administration of antibodies blocking the immune checkpoint molecules programmed cell death protein 1 (PD-1) or programmed cell death 1 ligand 1 (PD-L1) has evolved as a very promising treatment option for cancer patients. PD-1/PD-L1 inhibition has significantly enhanced expansion, cytokine secretion, and cytotoxic activity of CD4+ and CD8+ T lymphocytes, resulting in enhanced antitumor responses. Anti-PD-1 or anti-PD-L1 therapy has induced tumor regression and improved clinical outcome in patients with different tumor entities, including melanoma, non-small-cell lung cancer, and renal cell carcinoma. These findings led to the approval of various anti-PD-1 or anti-PD-L1 antibodies for the treatment of tumor patients. However, the majority of patients have failed to respond to this treatment modality. Comprehensive immune monitoring of clinical trials led to the identification of potential biomarkers distinguishing between responders and non-responders, the discovery of modes of treatment resistance, and the design of improved immunotherapeutic strategies. In this review article, we summarize the evolving landscape of biomarkers for anti-PD-1 or anti-PD-L1 therapy.

Extracorporeal photopheresis efficiently impairs the proinflammatory capacity of human 6-sulfo LacNAc dendritic cells.

BACKGROUND: Extracorporeal photopheresis (ECP) emerged as a promising treatment modality for steroid-refractory graft-versus-host disease (GVHD), which represents a major complication of allogeneic hematopoietic stem-cell transplantation. Dendritic cells (DCs) display an extraordinary capacity to induce T-cell responses and play a crucial role in the initiation and maintainance of GVHD. This study evaluated the direct impact of ECP on the proinflammatory capacity of 6-sulfo LacNAc (slan) DCs, representing a major subpopulation of human blood DCs. METHODS: SlanDCs were isolated from ECP-treated or untreated blood of healthy donors or GVHD patients by immunomagnetic isolation. The maturation of slanDC was determined by flow cytometry. Cytokine production of slanDCs was measured by enzyme-linked immunosorbent assay. SlanDC-mediated T-cell proliferation was evaluated by H-thymidine incorporation. SlanDC-mediated T-cell programming was determined by flow cytometry. RESULTS: ECP efficiently impairs the spontaneous maturation and secretion of proinflammatory tumor necrosis factor-alpha, interleukin-1beta, and interleukin-12 by slanDCs. Furthermore, ECP markedly inhibits slanDC-induced proliferation of CD4 and CD8 T cells and polarization of naïve CD4 T lymphocytes into Th1 cells. CONCLUSIONS: These novel findings indicate that ECP efficiently impairs the proinflammatory capacity of slanDCs, which may represent an important mechanism for the therapeutic efficiency of ECP in GVHD.