Workshop on immunotherapy combinations. Society for immunotherapy of cancer annual meeting Bethesda, November 3, 2011

Although recent FDA approvals on ipilimumab and sipuleucel-T represent major milestones, the ultimate success of immunotherapy approaches will likely benefit from appropriate combinations with other immunotherapeutic and/or non-immunotherapeutic approaches. However, implementation of ideal combinations in the clinic may still face formidable challenges in regulatory, drug-availability and intellectual property aspects. The 2011 SITC annual meeting hosted a workshop on combination immunotherapy to discuss: 1) the most promising combinations found in the laboratory; 2) early success of combination immunotherapy in clinical trials; 3) industry perspectives on combination approaches, and 4) relevant regulatory issues. The integrated theme was how to accelerate the implementation of efficacious combined immunotherapies for cancer patients. Rodent animal models are providing many examples of synergistic combinations that typically include more than two agents. However, mouse and human immunology differ in a significant number of mechanisms and hence we might be missing opportunities peculiar to humans. Nonetheless, incisive animal experimentation with deep mechanistic insight remains the best compass that we can use to guide our paths in combinatorial immunotherapy. Combination immunotherapy clinical trials are already in progress and preliminary results are extremely promising. As a key to translate promising combinations into clinic, real and “perceived” business and regulatory hurdles were debated. A formidable step forward would be to be able to test combinations of investigational agents prior to individual approval. Taking together the FDA and the industrial perspective on combinatorial immunotherapy, the audience was left with the clear message that this is by no means an impossible task. The general perception is that the road ahead of us is full of combination clinical trials which hopefully will bring clinical benefit to our cancer patients at a fast pace

Perspectives in melanoma: meeting report from the Melanoma Bridge (November 29th-1 December 1st, 2018, Naples, Italy).

Diagnosis of melanocytic lesions, correct prognostication of patients, selection of appropriate adjuvant and systemic therapies, and prediction of response to a given therapy remain very real challenges in melanoma. Recent studies have shown that immune checkpoint blockade that represents a forefront in cancer therapy, provide responses but they are not universal. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers they have yet to be fully characterized and implemented clinically. For example, advancements in sequencing and the understanding of the tumor microenvironment in melanoma have led to the use of genome sequencing and gene expression for development of multi-marker assays that show association with inflammatory state of the tumor and potential to predict response to immunotherapy. As such, melanoma serves as a model system for understanding cancer immunity and patient response to immunotherapy, either alone or in combination with other treatment modalities. Overall, the aim for the translational and clinical studies is to achieve incremental improvements through the development and identification of optimal treatment regimens, which increasingly involve doublet as well as triplet combinations, as well as through development of biomarkers to improve immune response. These and other topics in the management of melanoma were the focus of discussions at the fourth Melanoma Bridge meeting (November 29th-December 1st, 2018, Naples, Italy), which is summarised in this report

On complex-valued 2D eikonals. Part four: continuation past a caustic

Theories of monochromatic high-frequency electromagnetic fields have been designed by Felsen, Kravtsov, Ludwig and others with a view to portraying features that are ignored by geometrical optics. These theories have recourse to eikonals that encode information on both phase and amplitude -- in other words, are complex-valued. The following mathematical principle is ultimately behind the scenes: any geometric optical eikonal, which conventional rays engender in some light region, can be consistently continued in the shadow region beyond the relevant caustic, provided an alternative eikonal, endowed with a non-zero imaginary part, comes on stage. In the present paper we explore such a principle in dimension $2.$ We investigate a partial differential system that governs the real and the imaginary parts of complex-valued two-dimensional eikonals, and an initial value problem germane to it. In physical terms, the problem in hand amounts to detecting waves that rise beside, but on the dark side of, a given caustic. In mathematical terms, such a problem shows two main peculiarities: on the one hand, degeneracy near the initial curve; on the other hand, ill-posedness in the sense of Hadamard. We benefit from using a number of technical devices: hodograph transforms, artificial viscosity, and a suitable discretization. Approximate differentiation and a parody of the quasi-reversibility method are also involved. We offer an algorithm that restrains instability and produces effective approximate solutions.Comment: 48 pages, 15 figure

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

In-Fusion™ assembly: seamless engineering of multidomain fusion proteins, modular vectors, and mutations

In-Fusion™ can join any two pieces of DNA that have a 15-bp overlap at their ends. The result is equivalent to a recombination event at the ends of the DNAs. The 15-bp overlap may be engineered by inclusion in primers used to PCR amplify a segment of DNA. Originally described for inserting one piece of DNA into a restriction enzyme-digested plasmid, We have found In-Fusion can join four or more pieces of DNA in a single reaction. We used this insight to construct seamless fusion proteins, modular vectors with readily interchangeable segments, and novel mutagenesis strategies. Replacement In-Fusion can be used to delete any desired DNA segment in a plasmid and replace it with any desired new DNA segment without limitations on position or size