Immune checkpoint combinations from mouse to man

Abstract

The discovery that antibody blockade of the T cell co-inhibitory receptor cytotoxic T lymphocyte-associated protein 4 (CTLA-4) can restore tumor immunity against many murine transplantable tumors leading to complete rejection of established cancer forever changed the field of immunotherapy. In more robust murine models as well as human cancer, however, CTLA-4 blockade alone can slow tumor growth and extend patient survival, but is rarely curative. Subsequent studies have revealed a large family of T cell immune checkpoint receptors which tumors engage to shield themselves from host immunity. As with CTLA-4, blockade of one of these additional inhibitory receptors, programmed death 1, has led to remarkable therapeutic responses against tumors of multiple lineages. Checkpoint monotherapy has demonstrated that durable, immune-mediated cures of established metastatic cancers are possible, yet the percentage of patients experiencing these outcomes remains low due to both redundant mechanisms of immune suppression in the tumor and limiting toxicity associated with some therapies. Thus, extending the curative potential of immunotherapy to a larger percentage of patients with a broader spectrum of malignancies will likely require combinations of co-inhibitory blockade and co-stimulatory activation designed to peel back multiple layers of tumor immune suppression while at the same time minimizing immune-mediated toxicity. As over a dozen T cell immune checkpoints and an additional dozen more co-stimulatory receptors have now been described, the challenge before us is to identify the most advantageous combinations of these agents based on the knowledge of their underlying biology and preclinical studies in murine tumor models.

CTLA-4 Blockade Synergizes Therapeutically with PARP Inhibition in BRCA1-Deficient Ovarian Cancer

“…S1). Results from these experiments demonstrated limited benefit from CTLA-4 monotherapy, in keeping with prior reports (4, 5); however, treatment with the CTLA-4 antibody together with PARP inhibition resulted in a synergistic therapeutic effect with long-term tumor-free survival in a majority of animals (Fig. 4A).…”

“…Ovarian cancer has been identified as a rational target for immune therapy; however, these tumors have been considered relatively resistant to checkpoint blockade (3, 4). This is based on studies in murine models and clinical trials that showed limited response of ovarian tumors to CTLA-4 antibodies (5–7).…”

“…On the basis of this, and other studies indicating that enhanced tumor antigenicity sensitizes cancers to checkpoint blockade therapy, combinatorial treatment regimens using cytotoxic agents together with checkpoint inhibitors have been proposed to optimize clinical outcomes (4). With evidence that a subset of ovarian cancers associated with germline mutations in BRCA1/2 genes may be more immunogenic (9–11), we hypothesized that BRCA1 − tumors would be particularly vulnerable to checkpoint blockade.…”

Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade

“…In order to increase the response rate to checkpoint blockade, several combination therapies have been developed (Ai and Curran, 2015). Among them, the combination with anti-PD-1 and anti-Cytotoxic T Lymphocyte-associated Antigen-4 (CTLA-4) has shown the best improvement in clinical trials (Hammers et al, 2014; Postow et al, 2015; Wolchok et al, 2013).…”

Immune checkpoint targeting as anti-cancer immunotherapy: promises, questions, challenges and the need for predictive biomarkers at ASCO 2015

“…This reflects the work of at least two decades and the unravelling of complex regulatory pathways involved in the immune responses to cancer. Specifically, there has been a great deal of progress in our understanding of how T cell activation is controlled through "immune checkpoints" for the generation of adaptive immune responses to malignancy, and of inhibiting these interactions to achieve significant and clinically meaningful antitumour effects [1,2]. Currently (July 2015), the largest group of immunotherapy trials of the total of >250 registered at clinicaltrials.…”