Guiding tumor-associated macrophages to inhibit tumor growth and metastasis
A recent article, published in the journal Cancer Cell, has revealed a new approach to inhibiting tumor growth and metastasis, using a naturally occurring host protein termed histidine-rich glycoprotein (HRG).
Previous studies have demonstrated the ability of HRG to affect blood vessel formation (angiogenesis). Tumors cannot grow beyond a certain size (generally 1–2 mm3) owing to a lack of oxygen and essential nutrients. In order to continue growing and to spread to other tissues (metastasis), tumors can induce angiogenesis by secreting various growth factors, such as VEGF. Inhibiting angiogenesis in the tumor microenvironment is one of the many approaches in anticancer research.
In the present study, a research team led by Lena Claesson-Welsh (Uppsala University, Sweden) and Peter Carmeliet (Katholieke Universiteit Leuven, Belgium) has shed new light on HRGs mechanism of action, in which HRG modulates inflammatory cells termed tumor-associated macrophages (TAMs).
Tumor-associated macrophages mainly consist of M2 macrophages that support blood vessel formation, thus encouraging tumor growth and metastasis. On the other hand, M1 macrophages inhibit tumor growth by activating cytotoxic immune cells that kill the tumor. Therefore, steering TAMs from M2 type to antitumoral M1 type can be an attractive approach to treating cancers.
The research team demonstrated that HRG can transform inflammatory cells in the tumor from M2 to M1 macrophages, and that M1 macrophages can affect the spread of tumor cells to secondary organs. Using three different murine tumor models, they showed that tumors that produce HRG grow more slowly and do not spread into subsidiary tumors. The authors also showed that the amount of HRG is greatly reduced in many cancer types in humans.
The authors wrote: “By skewing TAM polarization away from the M2- to a tumor-inhibiting M1-like phenotype, HRG promotes antitumor immune responses and vessel normalization, effects known to decrease tumor growth and metastasis and to enhance chemotherapy. Skewing of TAM polarization by HRG relies substantially on downregulation of placental growth factor (PlGF).” PlGF downregulation prompts M2 macrophages to transform into M1 macrophages. M1 macrophages then activate cytotoxic immune cells that kill the tumor. Unlike M2, M1 cells do not support blood vessel formation, thus allowing for blood vessel normalization and tumor growth inhibition.
“Our study shows that the regulation of tumor-associated inflammation can be utilized to treat cancer and that there is a great potential to develop HRG into a drug for cancer treatment,” said Claesson-Welsh. “One significant finding is that HRG enhances the effect of chemotherapy in slowing down the growth of cancer.”
“The next step will be to find the binding sites for HRG on macrophages, so they can be used in developing drugs. We are also looking into how HRG levels in the blood change in cancer, in collaboration with surgeons at Uppsala University Hospital,” said Claesson-Welsh.
Sources: Rolny C, Mazzone M, Tugues S et al.: HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell DOI: 10.1016/j.ccr.2010.11.009 (2011) (Epub ahead of print); Uppsala University, Sweden: www.uu.se
Follicular lymphoma patients may benefit from rituximab maintenance therapy
Findings from a large, randomized trial of follicular lymphoma (PRIMA) have recently been published in the Lancet. In the study, patients who were receiving rituximab maintenance therapy for 2 years following immunochemotherapy were found to experience improved rates of progression-free survival compared with those not receiving rituximab maintenance therapy.
Rituximab plus chemoimmunotherapy has been successful in improving overall survival over the past 10 years and has become the standard first-line treatment for follicular lymphoma. Relapse usually occurs 3–5 years after completion of chemoimmunotherapy, and consequently the researchers based at Université Claude Bernard (Lyon, France) were keen to discover whether maintenance therapy could reduce this risk.
The study involved 1217 patients with previously untreated follicular lymphoma from 223 centers across 25 countries. Following induction, 1019 eligible patients who achieved a complete or partial response were then randomly assigned to either rituximab maintenance (505 patients) or no treatment (513) for 2 years.
A total of 71.5% of patients from the rituximab group achieved complete, or an unconfirmed complete, response after 2 years compared with 52.2% in the observation group, determined by clinical examination and CT scans. In addition, quality-of-life measurements recorded no group differences, and rituximab maintenance therapy was generally well tolerated.
However, the value of the results was questioned by Jonathan Friedberg (University of Rochester, NY, USA): “In an era of increased healthcare costs, what benefit is necessary to justify the cost of this maintenance strategy, which at my institution would cost Medicare more than US$60,000 per patient?”
Although long-term follow-up of the trial participants is required before rituximab maintenance can be recommended for all patients, the PRIMA trial has demonstrated that the treatment significantly improves progression-free survival in follicular lymphoma patients.
Source: Salles G, Seymour JF, Offner F et al.: Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a Phase III, randomised controlled trial. Lancet 377(9759), 42–51 (2011).
MedImmune to explore AMG 108 monoclonal antibody as treatment for inflammatory diseases
Amgen (CA, USA) has recently granted MedImmune (MD, USA) rights to develop AMG 108 worldwide, outside of Japan. AMG 108 is a novel, fully human monoclonal antibody to the IL-1 receptor, which will be explored by MedImmune for its potential against certain inflammatory diseases.
The antibody has been studied in multiple Phase I and II clinical trials. “Recent data indicates the importance of the IL-1 pathway in a variety of inflammatory conditions, and AMG 108 represents a compelling opportunity to explore this antibody‘s activity against various diseases for which patients need new treatment options,” said Bahija Jallal, MedImmune‘s executive vice president of research and development.
Source: MedImmune, MD, USA: www.medimmune.com
GlaxoSmithKline granted exclusive rights to IMP731, a novel therapeutic antibody for treatment of autoimmune diseases
Immutep SA (Orsay, France) has announced that it has signed a license agreement with GlaxoSmithKline (UK), granting GlaxoSmithKline exclusive worldwide rights to ImmuTune® IMP731 and any other antibodies that carry out the same function.
IMP731 is a cytotoxic antibody that specifically depletes lymphocyte-activation gene-3 (LAG-3)-positive T cells. Many autoimmune diseases are presented with chronically activated T cells, and LAG-3 is a marker for activated, long-lived effector–memory T cells.
Selective depression of pathogenic LAG-3-positive T cells is a new therapeutic approach that differs from simply blocking a function of these T cells (e.g., blocking the production of TNF-α, IL-6 or IL-23). In addition, the depression is specific to LAG-3-positive T cells, leading to targeted immunosuppression while other T-cell subsets (LAG-3-negative) are not affected. This approach should result in a significantly better side effect profile with a reduced risk of susceptibility to infections, when compared with classical immunosuppressants, such as corticoids or cyclosporine, through which all T cells are suppressed.
In preclinical models, low doses of IMP731 have demonstrated potency of T-cell-mediated inflammation. Such a targeted therapy that induces long-term effects with a minimum number of injections is a promising approach in many autoimmune diseases where self-antigens have activated T cells, such as rheumatoid arthritis and multiple sclerosis.
“We are very pleased to hand over the development of IMP731 to GlaxoSmithKline, with its commitment to bringing breakthrough therapies to patients,” said John Hawken, who is Immutep‘s chief executive officer. “For Immutep, the value created through this transaction will enable us to focus our resources on advancing our oncology assets, IMP321 and IMP701. IMP321 is ready for a Phase IIb/III trial in the chemoimmunotherapy of first-line metastatic cancer.”
Under the terms of the agreement, GlaxoSmithKline will assume all development responsibility and associated costs for IMP731. Immutep will receive an upfront payment and milestones of up to GB£64 million (US$100 million) and is eligible for single-digit, tiered royalties if all objectives are achieved.
Source: Immutep SA, France: www.immutep.com