Cell Checkpoint Inhibitors Research Articles

Cancer immunology – development of novel anti-cancer therapies

The vast majority of tumours are characterised by high frequencies of genetic and epigenetic alterations resulting in tumour-specific antigens, which may, in principle, be recognised by cytotoxic T cells. Though early clinical immunotherapy trials have yielded mixed results with ambiguous clinical benefit, cancer immunotherapy is now attracting increasing attention as a viable therapeutic option, mainly in melanoma and lung cancer, but increasingly also in other malignancies. In particular, recent therapeutic efforts targeting inhibitory receptors on T cells to overcome tumour-induced immune dysfunction have the potential to reshape current treatment standards in oncology. The clinical development has been pioneered by the antibody ipilimumab, which blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and has demonstrated survival benefit in two randomised landmark trials in melanoma. Capitalising on this success, the research on the clinical implication of T cell checkpoint inhibition has been boosted. Early clinical trials have demonstrated meaningful response rates, sustained clinical benefits with encouraging survival rates and good tolerability of next-generation checkpoint inhibitors, including programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors, across multiple cancer types. Attractive perspectives include the concurrent blockade of immunological (non-redundant) checkpoints, which has recently been demonstrated using combinations of immune checkpoint modulators themselves or with other therapies, such as chemotherapy, targeted therapy or radiotherapy. This article summarises the mechanism of action and subsequent clinical studies of immune checkpoint antibodies in oncology with a particular focus on melanoma and lung cancer.

823P - Sunitinib Pretreatment Does not Impair Tumor Infiltrating Lymphocyte (Til) Expansion but Reduces Intratumoral Content of Myeloid-Derived Suppressor Cells (Mdsc) in Metastatic Renal Cell Carcinoma

ABSTRACT Aim: Targeted therapy (TT), with e.g. suntinib, pazopanib or everolimus, has improved treatment outcome for metastasized renal cell carcinoma patients, but despite considerable effort in sequential or combined modalities, durable remissions do not occur. Immunotherapeutic approaches, like cytokine therapy with interleukin (IL)-2, T cell checkpoint inhibition (TcCB) or adoptive T cell therapies (ACT), can achieve long-term benefit or even cure. This raises the question of whether combining TT with TcCB or ACT could improve patients' outcomes. However, based on pre-clinical in vitro tests, sunitinib is thought to hamper T cell functions and possible increases intratumor myeloid-derived suppressor cells (MDSC) content. Methods: We therefore compared renal cell carcinoma (RCC) tumor material from patients either pretreated with sunitinib or not (sunitinib-naive) for ability to grow TIL form these tissues and for their content of regulatory T cells (Treg) and MDSC. Results: We found no impaired TIL expansion after sunitinib treatment, but wel reduced intratumoral MDSC content, while the amount of intratumoral Treg was not altered. Conclusions: Suntitinb is thus a good combination partner for ACT and/or TcCB, which could be extended by adding a Treg-altering agent. Disclosure: C. Blank: Advisory role for Roche, GSK, MSD, BMS, and Novartis. Research grant form Novartis; J.B.A.G. Haanen: Advisory role for Roche and GSK and research grant from GSK. All other authors have declared no conflicts of interest.

Correction: Potentiation of the Novel Topoisomerase I Inhibitor Indenoisoquinoline LMP-400 by the Cell Checkpoint and Chk1-Chk2 Inhibitor AZD7762

In this article (Cancer Res 2012:979–89), which was published in the February 15, 2012, issue of Cancer Research (1), the structure shown in Fig. 1A is incorrect. The correct structure is below. The authors regret this error.

Correction: Potentiation of the Novel Topoisomerase I Inhibitor Indenoisoquinoline LMP-400 by the Cell Checkpoint and Chk1-Chk2 Inhibitor, AZD7762

Correction: Potentiation of the Novel Topoisomerase I Inhibitor Indenoisoquinoline LMP-400 by the Cell Checkpoint and Chk1-Chk2 Inhibitor, AZD7762

Potentiation of the novel topoisomerase I inhibitor indenoisoquinoline LMP-400 by the cell checkpoint and Chk1-Chk2 inhibitor AZD7762.

Novel topoisomerase I (Top1) inhibitors are in clinical development to circumvent the drawbacks of camptothecins (CPT). Here, we report molecular investigations into LMP-400, an indenoisoquinoline Top1 inhibitor in phase 1 clinical trial, by itself and in combination with the cell-cycle checkpoint inhibitor AZD7762. We examined drug effects on DNA replication and killing of cancer cells and found that LMP-400 showed synergistic antiproliferative activity when combined with AZD7762 in human colon carcinoma cells. Inhibition of S-phase progression and bromodeoxyuridine incorporation were similarly induced by LMP-400 and CPT and were abrogated by AZD7762. Replication studied by single DNA molecule analyses and immunofluorescence microscopy (molecular combing) showed rapid inhibition of fork progression in response to LMP-400 treatment with subsequent recapitulation after AZD7762 addition. AZD7762 inhibited both the activation/autophosphosphorylation of Chk1 and Chk2 at nanomolar concentrations in LMP-400-treated cells. This potent dual inhibition of Chk1 and Chk2 by AZD7762 was below the drug concentrations required to abrogate cell-cycle inhibition and produce synergism with LMP-400. Also, the synergism was independent of Chk2 both in Chk2-complemented cells and Chk2 knockout cells, suggesting additional mechanisms for cell-cycle abrogation by AZD7762. Together, our findings show a rationale for combining cell-cycle checkpoint inhibitors with the novel non-CPT indenoisoquinoline Top1 inhibitors.