Immunology and Biotherapies

Abstract

Enhancing immune responses with immune-modulatory monoclonal antibodies directed to inhibitory immune receptors is a promising modality in cancer therapy. Clinical efficacy has been demonstrated with antibodies blocking inhibitory immune checkpoints such as cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) or PD-1/PD-L1. Treatment with ipilimumab, a fully human CTLA-4–specific mAb, showed durable clinical efficacy in metastatic melanoma; its mechanism of action is, however, only partially understood. This is a study of 29 patients with advanced cutaneous melanoma treated with ipilimumab. We analyzed peripheral blood mononuclear cells (PBMCs) and matched melanoma metastases from 15 patients responding and 14 not responding to ipilimumab by multicolor flow cytometry, antibody-dependent cell-mediated cytotoxicity (ADCC) assay, and immunohistochemistry. PBMCs and matched tumor biopsies were collected 24 h before (i.e., baseline) and up to 4 wk after ipilimumab. Our findings show, to our knowledge for the first time, that ipilimumab can engage ex vivo FcγRIIIA (CD16)-expressing, nonclassical monocytes resulting in ADCC-mediated lysis of regulatory T cells (Tregs). In contrast, classical CD14++CD16−monocytes are unable to do so. Moreover, we show that patients responding to ipilimumab display significantly higher baseline peripheral frequencies of nonclassical monocytes compared with nonresponder patients. In the tumor microenvironment, responders have higher CD68+/CD163+ macrophage ratios at baseline and show decreased Treg infiltration after treatment. Together, our results suggest that anti–CTLA-4 therapy may target Tregs in vivo. Larger translational studies are, however, warranted to substantiate this mechanism of action of ipilimumab in patients.

The BJC is owned by Cancer Research UK, a charity dedicated to understanding the causes, prevention and treatment of cancer and to making sure that the best new treatments reach patients in the clinic as quickly as possible.

Fig 1. Targets of antibody immune modulators (Page et al, 2014)

background:  

Immune modulation in cancer refers to a range of treatments aimed at harnessing a patient’s immune system to achieve tumour control, stabilisation, and potential eradication of disease. A novel therapeutic drug class called immune checkpoint-blocking antibodies modulate T-cell pathways that regulate T cells and have the potential to reinvigorate an antitumour immune response. Ipilimumab was the first FDA-approved immune checkpoint antibody licensed for the treatment of metastatic melanoma (MM) and blocks a checkpoint molecule called cytotoxic T-lymphocyte antigen 4 (CTLA-4).

methods:  

Herein we review the preclinical and clinical development of ipilimumab. We outline the mode of action of these agents and other immune checkpoint inhibitors, the management of their toxicities, and how to adequately assess response to treatment.

results:  

As a result of these data, a number of other antibodies that block novel checkpoint molecules including programmed death-1 (PD-1), and corresponding ligands such as programmed death ligand-1 (PD-L1) are under preclinical and clinical development, and have demonstrated activity in multiple tumour types.

conclusions:  

This review will summarise the mechanism of action and clinical development of immune checkpoint antibodies, as well as lessons learned in the management and assessment of patients receiving these agents.

Until recently, most immunotherapeutic approaches used to fight cancer were ineffective, counteracted by the tumour’s ability to evade immune attack. However, extensive research has improved our understanding of tumour immunology and enabled the development of novel treatments that can harness the patient’s immune system and prevent immune escape. Over the last few years, through numerous clinical trials and real-world experience, we have accumulated a large amount of evidence regarding the potential for long-term survival with immunotherapy agents in various types of malignancy. The results of these studies have also highlighted a number of recurring observations with immuno-oncology agents, including their potential for clinical application across a broad patient population and for both conventional and unconventional response patterns. Furthermore, given the numerous immune checkpoints that exist and the multiple mechanisms used by tumours to escape the immune system, targeting distinct checkpoint pathways using combination approaches is an attractive therapeutic strategy with the potential to further enhance the antitumour immune response.

Fig 1. Immuno-oncology agentsa in clinical development across multiple tumour types.aSelected therapies and tumour types are shown: additional agents are, for example in phase 1 studies in patients with solid tumours [12]. AML, acute myeloid leukemia; CLL, chronic lymphocytic leukaemia; CRC, colorectal cancer; CRPC, castration-resistant prostate cancer; CTLA-4, cytotoxic T-lymphocyte antigen-4; GIST, gastrointestinal stromal tumour; HCC, hepatic cell carcinoma; LAG-3, lymphocyte activation gene 3; mAb, monoclonal antibody; NHL, non-Hodgkin lymphoma; NSCLC, non-small cell lung cancer; PC, prostate cancer; PD1, programmed death 1; RCC, renal cell carcinoma; SCLC, small cell lung cancer.

Ascierto and Marincola Journal of Translational Medicine 2014 12:141   doi:10.1186/1479-5876-12-141

TIL Technology 

In the early stages of cancer, special immune cells known as tumor infiltrating lymphocytes (TILs) migrate to the tumor and launch an attack.  However, this effect is usually short-lived because cancer adapts to evade immune detection and suppress immune response. Lion’s TIL technology is designed to overcome the immunosuppressive effects of cancer, while leveraging and enhancing the power of TILs to treat, and potentially cure, all solid tumors.

Our TIL technology has demonstrated robust efficacy in Phase 2 clinical trials, indicating objective response rates of 49% in Stage 4 metastatic melanoma.  Based on an adoptive cell therapy regimen developed by Steven A. Rosenberg, MD, chief of surgery at National Cancer Institute (NCI), it is currently in use as a physician-sponsored investigational treatment for Stage IV metastatic melanoma at NCI, MD Anderson Cancer Center, and the H. Lee Moffitt Cancer & Research Institute.