Immunology and Biotherapies

Abstract

The concept of immunotherapy as a modality to treat cancer was recognized more than a hundred years ago. High-dose interleukin-2 (IL-2) was one of the first agents to demonstrate that the host's immune system can be harnessed to treat even advanced malignancy, as was shown in a subset of patients with renal cancer and melanoma. Many tumours are immunogenic and provoke a host immune response, but this is normally not sufficient to overcome host tolerance. For decades now, researchers have tried various methods to enhance host immunological responses, such as the use of non-specific immunotherapeutic cytokines, tumour vaccines, adoptive immunotherapy and the use of monoclonal antibodies against a wide variety of molecules. This review discusses the principles of the various types of immune therapy and focuses on some of the recent developments and successes in treatment. The article concentrates on the applications of immunotherapy in solid tumours, though it has immense value in haematological cancers.

Via Krishan Maggon

Cancer Gene Therapy is the essential gene therapy resource for cancer researchers and clinicians, keeping readers up to date with the latest developments in gene therapy for cancer.

Via Krishan Maggon

#TIL's Genetically #Engineered w/Inducible Gene Encoding IL-12 for #Immunotherapy of Metastatic #Melanoma http://t.co/ABuiy4QodT #health

 

Abstract

Purpose: Infusion of interleukin-12 (IL-12) can mediate anti-tumor immunity in animal models, yet its systemic administration to patients with cancer results in minimal efficacy and severe toxicity. Here, we evaluated the anti-tumor activity of adoptively transferred human tumor infiltrating lymphocytes (TIL) genetically engineered to secrete single-chain IL-12 selectively at the tumor site. Experimental Design:Thirty-three patients with metastatic melanoma were treated in a cell-dose escalation trial of autologous TIL transduced with a gene encoding a single chain IL-12 driven by a nuclear factor of activated T cells promoter (NFAT.IL12). No IL-2 was administered. Results:The administration of 0.001-0.1 X 109 NFAT.IL12 transduced TIL to 17 patients resulted in a single objective response (5.9%). However, at doses between 0.3-3 X 109 cells, 10 of 16 patients (63%) exhibited objective clinical responses. The responses tended to be short and the administered IL-12 producing cells rarely persisted at one month. Increasing cell doses were associated with high serum levels of IL-12 and gamma-interferon as well as clinical toxicities including liver dysfunction, high fevers and sporadic life threatening hemodynamic instability. Conclusions:In this first-in-man trial, administration of TIL transduced with an inducible IL-12 gene mediated tumor responses in the absence of IL-2 administration using cell doses 10-100 fold lower than conventional TIL. However, due to toxicities, likely attributable to the secreted IL-12, further refinement will be necessary before this approach can be safely utilized in the treatment of cancer patients.

Via Krishan Maggon

Immunotherapies for cancer are demonstrating increasing success. These agents can amplify existent antitumour immunity or induce durable antitumour immune responses in a wide array of cancers. The spectrum of immunotherapeutics is broad, spanning monoclonal antibodies and their derivatives, tumour vaccines, and adoptive therapies using T cells and natural killer cells.

Only a small number of immunotherapies have been tested in paediatric cancers, but impressive antitumour effects have already been observed. Mononclonal antibodies targeting GD2 that induce antibody-dependent cell-mediated cytotoxicity improve survival in high-risk neuroblastoma. Bi-specific monoclonal antibodies that simultaneously target CD19 and activate T cells can induce remission in acute B-cell lymphoblastic leukaemia (B-ALL) and adoptive immunotherapy using T cells genetically engineered to express chimeric antigen receptors targeting CD19 induce impressive responses in B-ALL. Efforts are underway to generate and test new immunotherapies in a wider array of paediatric cancers. Major challenges include a need to identify immunotherapy targets on the most lethal childhood cancers, to expand availability of technology-intense platforms, such as adoptive cell therapy, to optimize management of novel toxicities associated with this new class of cancer therapies and to determine how best to incorporate these therapies into standard treatment paradigms.

Via Krishan Maggon