Immunology and Biotherapies

Highlights

 

•Anticancer therapies alter the composition, phenotype, and function of immune cells.•The immune system is a major regulator of the success of anticancer therapy.•Immunotherapy and immunomodulatory agents often synergize with conventional therapies.•Resistance mechanisms following immunotherapy and immunodulatory agents are not fully defined.•Targeting both cancer cells and immune cells may be the key to fight metastasis.

 

Conventional anticancer therapies, such as chemotherapy, radiotherapy, and targeted therapy, are designed to kill cancer cells. However, the efficacy of anticancer therapies is not only determined by their direct effects on cancer cells but also by off-target effects within the host immune system. Cytotoxic treatment regimens elicit several changes in immune-related parameters including the composition, phenotype, and function of immune cells. Here we discuss the impact of innate and adaptive immune cells on the success of anticancer therapy. In this context we examine the opportunities to exploit host immune responses to boost tumor clearing, and highlight the challenges facing the treatment of advanced metastatic disease.

Via Krishan Maggon

Development of antibody-based c-Met inhibitors for targeted cancer therapy Dongheon Lee, Eun-Sil Sung, Jin-Hyung Ahn, Sungwon An, Jiwon Huh, Weon-Kyoo You Hanwha Chemical R&D Center, Biologics Business Unit, Daejeon, Republic of Korea Abstract:...

Via Krishan Maggon

Need for Simultaneous Multi-targeting

Attempting to therapeutically shut down a tumor cell signaling pathway on a single tumor cell may not be enough when dealing with most cancers. When one pathway is blocked, cancer cells may adapt and become dependent on alternate pathway(s) or other cancer cells may continue to grow and become dominant over time due to different dependencies. In essence it is often the case that mechanisms other than those directly targeted become the drivers of a tumor's resistance to current therapy. New approaches are needed that simultaneously target multiple cell signaling pathways and multiple cell types to increase the chance of significant clinical benefit. 

Multi-targeting by mAb Mixtures

The mAb mixture approach enables Symphogen to develop truly innovative and differentiated products, each simultaneously directed against multiple biological targets.  We believe that successfully attacking multiple targets and cells with different dependencies, such as tumor cells, stromal cells, immune cells, and/or ligands, provide mAb mixtures with the advantages of greater efficacy and the ability to prevent tumor resistance associated with tumor heterogeneity and adaptability.

 

Unique Mechanism of Action with mAb Mixtures

Symphogen's research has shown that new and unique mechanisms of action can be obtained with carefully selected mAb mixtures against cancer targets. The Sym004 mAb mixture targeting a receptor tyrosine kinase (EGFR) is one such example where synergistic action of two mAbs cause extensive receptor cross-linking on the cell, while also inducing secondary effector functions to a much greater extent than seen with monoclonal antibodies. Such antibody induced cross-linking of the receptors leads to very efficient internalization of the receptors and subsequent receptor elimination. As a consequence, tumor growth dependent on the receptor targeted by Sym004 is effectively shut down. Symphogen has shown that receptor elimination leads to sustained tumor suppression in a broad range of receptor-dependent animal tumor models superior to that of existing monoclonal antibodies. Receptor elimination by Sym004 has been well-documented in preclinical models and confirmed in ongoing clinical trials. 

Via Krishan Maggon

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.

Via Krishan Maggon

Engineered T cell CAR therapy

 

A revolution is taking place in the field of adoptive immunotherapy, where T cells armed with a Chimeric Antigen Receptor (CAR) are being used to fight cancerous cells. Genome engineering is at the heart of this revolution. This groundbreaking technology relies mainly on the use of engineered nucleases and makes it possible to modify the genome of the T cell to give it new properties. Specifically, the engineered T cell can be transformed into an allogeneic product, or it can resist existing cancer treatments or even overcome checkpoint inhibition. Genome engineering is regarded as one of the most important breakthroughs of recent years, and is about to revolutionize immunotherapy. 

Decades of research have shown that it is possible to improve the ability of T cells to fight diseases by genome engineering. For example, T cells can be engineered by adding a new gene (called a chimeric antigen receptor or CAR) that will boost their ability to recognize and destroy cancer cells. Another possibility for T cells is to inactivate an existing gene that damages the immune response.

The possibilities provided by T cell genome engineering are endless. Very sophisticated strategies can be designed at will to open the door for a new era of treatments in indications such as infectious diseases, autoimmune diseases, and cancer.

 

Chimeric Antigen Receptors (CARs) are artificial molecules that, when present at the surface of immune effector cells, will enable them to recognize a desired protein (antigen) and trigger the killing of cells harboring this antigen at their surface (target cells).

These receptors are becoming one of the most promising approaches to fight cancer, through the development of adoptive cell transfer therapies. Indeed, immune cells (most usually T-lymphocytes) can be engineered to express a CAR able to recognize proteins present at the surface of cancer cells. Upon cell-to-cell contact between effector and targeted cells, antigen recognition will activate the effectors, giving them the signal to attack their targets, and leading ultimately to the killing of cancer cells.

CARs are constructed by assembling domains from different proteins, each of which enables the chimeric molecule to carry out specific functions. The most common CAR architecture comprises an extracellular domain containing a region that recognizes the targeted antigen and a spacer region that links it to the transmembrane domain (the part of the protein that spans the cellular membrane). This is then followed by an intracellular domain, responsible for transmitting an activation signal to the cell upon antigen recognition, causing the CAR-engineered cell to attack the tumor cell.

The target-binding moiety is usually derived from an antibody, while the intracellular portion can include, besides the domain leading to cell activation and cytotoxic response, one or more domains from co-stimulatory receptor proteins that could enhance the proliferative capacity and survival of the “therapeutic” cells.

Cellectis is currently developing a collection of CARs targeting antigens present on cells from various types of cancer, as well as a proprietary multi-chain architecture of these artificial receptors, aiming to further increase the efficacy of adoptive cell therapies in the future.

CELLECTIS’ UCART19 RECEIVES ADVANCED-THERAPY MEDICINAL PRODUCT CLASSIFICATION FROM EMAJune 23, 2014

 

READ MORE READ THE PRESS RELEASEPFIZER AND CELLECTIS ENTER INTO GLOBAL STRATEGIC CANCER IMMUNOTHERAPY COLLABORATIONJune 18, 2014 

Via Krishan Maggon

MT @NatRevClinOncol A shed NKG2D ligand that promotes NK cell activation & #tumor rejection http://t.co/fjxcQRyDGS #immunotherapy #cancer

 

Abstract

 

Immune cells, including natural killer (NK) cells, recognize transformed cells and eliminate them in a process termed immunosurveillance. It is thought that tumor cells evade immunosurveillance by shedding membrane ligands that bind to the NKG2D activating receptor on NK cells and/or T cells, and desensitize these cells. In contrast, we show that in mice, shedding of MULT1, a high affinity NKG2D ligand, causes NK cell activation and tumor rejection. Recombinant soluble MULT1 stimulated tumor rejection in mice. Soluble MULT1 functions, at least in part, by competitively reversing a global desensitization of NK cells imposed by engagement of membrane NKG2D ligands on tumor-associated cells, such as myeloid cells. The results overturn conventional wisdom that soluble ligands are inhibitory, and suggest a new approach for cancer immunotherapy.

Via Krishan Maggon

Abstract

Antibody-based therapy of various human malignancies has shown efficacy in the past 30 years and is now one of the most successful and leading strategies for targeted treatment of patients harboring hematological malignancies and solid tumors. Antibody–drug conjugates (ADCs) aim to take advantage of the affinity and specificity of monoclonal antibodies (mAbs) to selectively deliver potent cytotoxic drugs to antigen-expressing tumor cells. Key parameters for ADC include choosing the optimal components of the ADC (the antibody, the linker and the cytotoxic drug) and selecting the suitable cell-surface target antigen. Building on the success of recent FDA approval of brentuximab vedotin (Adcetris®) and ado-trastuzumab emtansine (Kadcyla®), ADCs are currently a class of drugs with a robust pipeline with clinical applications that are rapidly expanding. The more ADCs are being evaluated in preclinical models and clinical trials, the clearer are becoming the parameters and the challenges required for their therapeutic success. This rapidly growing knowledge and clinical experience are revealing novel modalities and mechanisms of resistance to ADCs, hence offering plausible solutions to such challenges. Here, we review the key parameters for designing a powerful ADC, focusing on how ADCs are addressing the challenge of multiple drug resistance (MDR) and its rational overcoming.

Via Krishan Maggon

Highlights

 

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Mast cells are found in large numbers at solid tumor sites and can have both pro-tumorigenic and anti-tumorigenic roles.

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Multiple pathways, including hypoxia, adenosine, TLR, antibody and complement, can activate mast cells in solid tumors.

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Activated mast cells recruit immune effector and regulatory cells and mobilize dendritic cell responses.

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Mast cells are excellent targets for cancer immunotherapy due to their location, prolonged lifespan and radio-resistance.

 

Abstract

Mast cells have historically been studied mainly in the context of allergic disease. In recent years, we have come to understand the critical importance of mast cells in tissue remodeling events and their role as sentinel cells in the induction and development of effective immune responses to infection. Studies of the role of mast cells in tumor immunity are more limited. The pro-tumorigenic role of mast cells has been widely reported. However, mast cell infiltration predicts improved prognosis in some cancers, suggesting that their prognostic value may be dependent on other variables. Such factors may include the nature of local mast cell subsets and the various activation stimuli present within the tumor microenvironment. Experimental models have highlighted the importance of mast cells in orchestrating the anti-tumor events that follow immunotherapies that target innate immunity. Mast cells are long-lived tissue resident cells that are abundant around many solid tumors and are radiation resistant making them unique candidates for combined treatment modalities. This review will examine some of the key roles of mast cells in tumor immunity, with a focus on potential immunotherapeutic interventions that harness the sentinel role of mast cells.

Via Krishan Maggon

Via Krishan Maggon