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Gulley J.L.,U.S. National Cancer Institute | Drake C.G.,Johns Hopkins University | Drake C.G.,Johns Hopkins Kimmel Cancer Center
Clinical Cancer Research | Year: 2011

A surge of interest in therapeutic cancer vaccines has arisen in the wake of recent clinical trials suggesting that such vaccines can result in statistically significant and clinically meaningful improvements in overall survival - with substantially limited side effects compared with chemotherapy - in patients with metastatic castration-resistant prostate cancer. One of these trials led to the registration of sipuleucel-T, the first therapeutic vaccine to be approved for cancer patients. In this review we highlight emerging patterns from clinical trials that suggest a need for more-appropriate patient populations (i.e., with lower tumor volume and less-aggressive disease) and endpoints (i.e., overall survival) for studies of immunotherapy alone, as well as biologically plausible explanations for these findings. We also explore the rationale for ongoing and planned studies combining therapeutic vaccines with other modalities. Finally, we attempt to put these findings into a practical clinical context and suggest fertile areas for future study. Although our discussion focuses on prostate cancer, the concepts we address most likely have broad applicability to immunotherapy for other cancers as well. ©2011 AACR.

Cancer researchers have long observed the value of treating patients with combinations of anti-cancer drugs that work better than single drug treatments. Now, in a new study using laboratory-grown cells and mice, Johns Hopkins scientists report that a method they used to track metabolic pathways heavily favored by cancer cells provides scientific evidence for combining anti-cancer drugs, including one in a nanoparticle format developed at Johns Hopkins, that specifically target those pathways. "We have to hit cancer cells from more than one angle, and that's made it important to learn how to combine drugs that hit the right combination of pathways," says Anne Le, M.D., H.D.R., assistant professor of pathology at the Johns Hopkins University School of Medicine and member of the Johns Hopkins Kimmel Cancer Center. Le says that the study of so-called metabolomics to track biochemical reactions in cancer and other cells should help scientists decide how best to combine drugs. A report of the scientists' work will appear online the week of Aug. 22 in Proceedings of the National Academy of Sciences. For the study, Le and her collaborators at Johns Hopkins, including Barbara Slusher, Ph.D., an expert in drug discovery, and Justin Hanes, Ph.D., a nanomedicine expert, started with an experimental drug called BPTES and injected it in mice with implanted human pancreatic tumors. BPTES has been used in animal models for a variety of cancers but has not substantially reduced tumor sizes, probably because the drug concentration in tumor tissue is not high enough when using conventional drug formulation methods, say the scientists. With this in mind, scientists from the Center for Nanomedicine at Johns Hopkins, led by Hanes, encapsulated the BPTES in a nanoparticle capsule coated in polyethylene glycol, a molecule used widely in medicines and industrial products, using a method they developed to provide a more uniform coating. The nanoparticle, according to the scientists, helps the drug slip through capillaries near cancer cells and remain within the tumor longer than it would otherwise. After 16 days, eight mice treated with encapsulated BPTES had tumors half the size of another eight mice treated with nanoparticles containing no drug. BPTES not encased in the nanoparticle delivery system had little effect on tumor size in 12 human tumor-bearing mice. "This shows that the nanoparticle-encapsulated drug is more effective in tumor reduction than the drug alone in these animal models," says Le. But their overriding interest in BPTES, says Slusher, was in how it works: by blocking the production of glutamine, an amino acid that acts as a building block of cells and is used frequently by pancreatic cancers to create more cancer cells. When the Johns Hopkins scientists saw that their nanoparticle-encapsulated version of BPTES shrunk mice tumors by half, Le and her colleagues searched for what major metabolic pathway was driving the growth of the remaining half of the tumor. To find it, the scientists injected the eight tumor-bearing mice with high levels of labeled glutamine and glucose, another metabolic compound commonly linked to the growth of pancreatic cancer cells. They then traced the compounds' biochemical breakdown through the mice and found that the remaining tumor cells had high amounts of lactate, an end product of the glucose pathway. With this information, the scientists tested the glucose-blocking anti-diabetes drug metformin, combined with the nanoparticle-encapsulated BPTES, on another eight mice implanted with human pancreatic tumors. The drug combination shrunk tumors by at least 50 percent more than those treated with either drug alone. Researchers elsewhere have been testing metformin in pancreatic cancer patients with little success, says Le, despite indications that it's a good candidate to treat glucose-dependent tumors. "But it appears the key may be to combine it with other drugs to shut off multiple key pathways in those tumors," she adds. The scientists have filed a patent for the technology associated with nanoparticle-encapsulated BPTES. The drug's chemical name is bis-2-(5-phenylacetamido-1,2.4-thiadiazol-2yl)ethyl sulfide.

Goldberg M.V.,Johns Hopkins Kimmel Cancer Center
Current topics in microbiology and immunology | Year: 2011

LAG-3 (CD223) is a cell surface molecule expressed on activated T cells (Huard et al. Immunogenetics 39:213-217, 1994), NK cells (Triebel et al. J Exp Med 171:1393-1405, 1990), B cells (Kisielow et al. Eur J Immunol 35:2081-2088, 2005), and plasmacytoid dendritic cells (Workman et al. J Immunol 182:1885-1891, 2009) that plays an important but incompletely understood role in the function of these lymphocyte subsets. In addition, the interaction between LAG-3 and its major ligand, Class II MHC, is thought to play a role in modulating dendritic cell function (Andreae et al. J Immunol 168:3874-3880, 2002). Recent preclinical studies have documented a role for LAG-3 in CD8 T cell exhaustion (Blackburn et al. Nat Immunol 10:29-37, 2009), and blockade of the LAG-3/Class II interaction using a LAG-3 Ig fusion protein is being evaluated in a number of clinical trials in cancer patients. In this review, we will first discuss the basic structural and functional biology of LAG-3, followed by a review of preclinical and clinical data pertinent to a role for LAG-3 in cancer immunotherapy.

Drake C.G.,Johns Hopkins Kimmel Cancer Center
Nature Reviews Immunology | Year: 2010

Advances in basic immunology have led to an improved understanding of the interactions between the immune system and tumours, generating renewed interest in approaches that aim to treat cancer immunologically. As clinical and preclinical studies of tumour immunotherapy illustrate several immunological principles, a review of these data is broadly instructive and is particularly timely now that several agents are beginning to show evidence of efficacy. This is especially relevant in the case of prostate cancer, as recent approval of sipuleucel-T by the US Food and Drug Administration marks the first antigen-specific immunotherapy approved for cancer treatment. Although this Review focuses on immunotherapy for prostate cancer, the principles discussed are applicable to many tumour types, and the approaches discussed are highlighted in that context. © 2010 Macmillan Publishers Limited. All rights reserved.

Drake C.G.,Johns Hopkins Kimmel Cancer Center
Annals of Oncology | Year: 2012

Combination immunotherapy approaches involving radiation, chemotherapy, androgen manipulation and T-cell modulation have been studied extensively in animal models, setting the stage for clinical trials. Radiation therapy, in particular, is an interesting modality in this regard, leading to synergistic efficacy when used in combination with immunotherapies in several models. Chemotherapy, the foundation of treatment of metastatic disease, may also augment the immune response to cancer; however, the potential immunosuppressive effects of chemotherapy render issues of dosing and timing critical. Perhaps, the most exciting combinatorial approach may be the co-administration of multiple immunological treatments. For example, in preclinical investigations, combined blockade of programmed death-1 (PD1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), which have key roles in the negative regulation of T-cell activation, has been shown to enhance antitumour immune responses compared with either agent alone. Taken together, the available data provide a strong rationale for initiating combination clinical trials, but lend a note of caution in that issues of dosing and timing likely require careful exploration in a phase II setting. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

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