Defining the Critical Hurdles in Cancer Immunotherapy

ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer

Genetics of graft-versus-host disease, I. A locus on Chromosome 1 influences development of acute graft-versus-host disease in a major histocompatibility complex mismatched murine model

Graft-versus-host disease (GVHD) is the major complication occurring after bone marrow transplantation. The severity of GVHD varies widely, with this variation generally being attributed to variation in the degree of disparity between host and donor for minor histocompatibility antigens. However, it is also possible that other forms of polymorphism, such as polymorphisms in immune effector molecules, might play a significant role in determining GVHD severity. In order to investigate this hypothesis, we are studying the genetic factors that influence GVHD development in a murine model. We here report the first results of this analysis, which demonstrate that a locus on Chromosome 1 of the mouse, and possibly also a locus on Chromosome 4, exert considerable influence over the development of one aspect of acute GVHD – splenomegaly – in a parent→F1 murine model. These results demonstrate that non-MHC genes can exert quite significant effects on the development of GVHD-associated pathology and that gene mapping can be used as a tool to identify these loci. Further analysis of such loci will allow identification of the mechanism whereby they influence GVHD and may lead in the future to improved selection of donors for human bone marrow transplantation