An investigational vaccine for non-Hodgkin‘s lymphoma (NHL) is now being tested in human subjects. This is the first time that proteins obtained from tobacco plants using magnICON® (Hamburg, Germany) technologies are undergoing clinical testing.
Idiotype vaccination is referred to as active immunotherapy and, unlike most other biological therapies, is specific to the individual patient. Patient-specific vaccines are produced in a pilot plant operated by the Bayer‘s subsidiary Icon Genetics (Halle, Germany). The objective of the therapy is to activate the patient‘s immune system, enabling the malignant cells to be targeted and destroyed by the body‘s own defense system.
“This personalized vaccine is being developed with the aim of keeping patients who have responded well to chemotherapy in complete remission,” explained Detlef Wollweber, head of Bayer Innovation GmbH. “In other words, it should prevent a recurrence of the tumor. The initiation of this clinical trial also demonstrates that our magnICON technology is suitable for manufacturing proteins for potential pharmaceutical applications.”
Non-Hodgkin‘s lymphoma is a type of malignant disease that occurs within the lymphatic system, and it is the fifth most common cause of death due to cancer. The overall prevalence of NHL in the EU is approximately 230,000, with an annual incidence of approximately 70,000 new cases. Follicular lymphoma is one of the most common types of indolent NHL, accounting for 25–30% of all NHLs. It is a type of cancer that is long lasting and difficult to treat.
The magnICON® technology is a new process for the rapid production of high yields of recombinant proteins, such as biopharmaceuticals, in tobacco plants. The plant is not genetically modified; the blueprint for the required product is inserted temporarily into the plant using a species of Agrobacterium and distributed throughout the plant cells. The protein is subsequently extracted from the plant‘s leaves in a very pure form.
“The goal of cancer therapy in the future will be to tailor treatment to the individual patient as far as possible,” said John Butler-Ransohoff, project manager for Plant-made Pharmaceuticals at Bayer. “Hematological tumors such as B-cell lymphomas are a good starting point for the further development of personalized medicine because the idiotypic antibodies formed by the lymphomas are highly specific tumor markers.”
The focus of this current clinical study in volunteers who have NHL is on the safety, tolerability and immunological effects of the vaccine. In this study, 20 patients will each be given six subcutaneous injections of the personalized vaccine over a 6-month period. The humoral and cellular immune responses in these patients will subsequently be characterized in the University of Navarra. If the results of this study are positive, an application will be made to carry out a Phase III study for registration purposes. The Phase I clinical study, which has now started, is being performed at the renowned University of Texas Southwestern Medical Center in Dallas (TX, US). The study is being coordinated locally by DAVA Oncology.
Source: Bayer Innovation: www.bayer.com
A research group led by Satya Dandekar from the University of California Davis (CA, USA) have demonstrated that inducing CD8+ T cells to kill HIV-infected cells – the most-studied approach in developing a HIV therapeutic vaccine – is not sufficient for a successful vaccine.
Dandekar and collaborators at University of California Berkeley and University of California San Diego (CA, USA) used the SIV-infected rhesus macaque model, which has the same disease that HIV causes in humans. Following the depletion of CD8+ T cells, SIV-infected monkeys showed an increased amount of virus, confirming the essential role of CD8+ T cells in controlling SIV.
The researchers then treated the monkeys with tenofovir and emtricitabine, the same antiretroviral combination used for HIV-infected patients. SIV levels decreased following drug treatment in monkeys depleted of CD8+ T cells. However, the rate and degree of viral reduction is similar in monkeys with intact CD8+ T cells, suggesting that the elimination of CD8+ T cells did not affect the lifespan of SIV-infected cells. If these cytotoxic T cells killed SIV-infected cells effectively, the viral reduction would have been faster in monkeys with intact CD8+ T cells.
“CD8+ T cells are vital to an immune system response to viruses, but we clearly don‘t know all the factors that make that possible,” said co-author Joseph Wong. “We hope our finding stimulates a better understanding of what constitutes an effective immune response against HIV.”
“The cytotoxic activity of CD8+ T cells by itself is not sufficient to provide ongoing protection from HIV because other virus-suppressive factors produced by these cells are involved,” said Dandekar. “The dominant role of these cells in controlling viral infection has yet to be found and may not be entirely linked to their direct-killing abilities. These findings provide us a new direction in identifying the suppressive factors that can be used to prevent or halt HIV infection.”
The finding was published in the January issue of the journal PLoS Pathogens. ‘Our findings support a dominant role for non-cytotoxic effects of CD8+ T cells on control of pathogenic lentiviral infection and suggest that cytotoxic effects, if present, are limited to early, preproductive stages of the viral life cycle,‘ the authors concluded.
In the same issue of the journal, work from a different group of researchers led by Guido Silvestri from the University of Pennsylvania (PA, USA) also arrived at the same conclusion. ‘[Our result] indicates that the presence of CD8+ lymphocytes does not result in a noticeably shorter lifespan of productively SIV-infected cells, and thus that direct cell killing is unlikely to be the main mechanism underlying the antiviral effect of CD8+ T cells in SIV-infected macaques with high virus replication.‘
‘Given the enormous effort invested in the development of HIV vaccines specifically directed at inducing CD8+ T cell responses, it is somewhat disconcerting to admit that CD8+ T cell function in HIV remains a “known unknown”‘, wrote Miles Davenport and Janka Petravic from University of New South Wales, Australia, in a complementary article.
Sources: Wong JK, Strain MC, Porrata R et al.: In vivo CD8+ T-cell suppression of SIV viremia is not mediated by CTL clearance of productively infected cells. PLoS Pathog. 6(1), E1000748 (2010); Klatt NR, Shudo E, Ortiz AM et al.: CD8+ lymphocytes control viral replication in SIVmac239-infected rhesus macaques without decreasing the lifespan of productively infected cells. PLoS Pathog. 6(1), E1000747 (2010); Davenport MP, Petravic J: CD8+ T cell control of HIV – a known unknown. PLoS Pathog. 6(1), E1000728 (2010); UC Davis Health System, CA, USA: www.ucdmc.ucdavis.edu/newsroom
A new strategy to make embryonic stem-cell transplant rejection less likely has been detailed in a mouse study involving the fusion of bone marrow cells and embryonic stem cells. The fused cells contain DNA from the host and the recipient, and are therefore potentially able to avoid rejection by the immune system without the need for drugs.
“Our study shows that transplanted bone marrow cells fuse not only with bone marrow cells of the recipient, but with non-hematopoietic cells, suggesting that if we can understand the process of cell fusion better, we may be able to target certain organ injuries with the patient‘s own bone marrow cells and repair the tissues,” predicted Nicholas Zavazava, a researcher from the University of Iowa (IA, USA) who was involved in the work.
Although further study is required, there is a possibility that bone marrow cells could be fused to transplant organs to prevent rejection by the recipient or to reduce the amount of immunosuppressive drugs required after transplantation. In addition, they could be fused to damaged organs to support regeneration.
Gerald Weissmann, editor-in-chief of the FASEB Journal where the article was published thinks that these findings could have far reaching consequences. “This research uses bone marrow cells to fuse with a patient‘s tissues so that nothing transplanted is rejected by our immune systems, and brings universal graft survival closer to reality.”
The authors concluded that “these data suggest that cell fusion is ubiquitous after cellular transplants and that the subsequent sharing of genetic material between the fusion partners affects cellular survival and function.” They also noted that “fusion between tumor cells and bone marrow cells could have consequences for tumor malignancy.”
Source: Bonde S, Pedram M, Stultz R, Zavazava N: Cell fusion of bone marrow cells and somatic cell reprogramming by embryonic stem cells. FASEB J. 24 (2), 364 (2010).
In a recent paper published in the Journal of Experimental Medicine, a team of researchers explain their findings on research into the conditions required for T-cell development.
T-cell development is complex and occurs in the thymus, where progenitor hematopoetic stem cells undergo a process of differentiation to become thymocytes, which will continue to develop into T cells.
Activity of the thymus is high during early life and childhood; however, this starts to decline after the onset of puberty, leading to a reduction in T-cell production.
In most healthy individuals, this does not lead to any problems; however, after chemotherapy or radiotherapy, thymocyte levels drop significantly and lead to immunosuppression. Infections such as HIV, which target a subset of T cells, or lymphomas, cancers that start in the lymphocytes, also lead to reduction in T-cell numbers, leaving the infected individual vulnerable to opportunistic pathogens and cancer.
At present, bone marrow transplant can be used to try and counter this decline in T-cell numbers but it can take up to 2 years for the cell population numbers to recover.
Much interest is, therefore, focused on T-cell reconstitution for therapeutic purposes. Progenitor cells are cultured in vitro with ‘feeder cells‘, which produce the factors required for T-cell development and allow the cells to be produced in the laboratory. Unfortunately, this type of production leads to contamination of the T cells by the feeder cells, thus limiting their usefulness.
In their paper, the research group, which included Michelle Janas of the Babraham Institute (Cambridge, UK), described a way of producing immature T cells without the need for feeder cells.
“One of the challenges for the scientific community is to reproduce the process of T-cell development in the laboratory,” said Janas. “The generation of T cells in culture is currently possible, but requires supporting feeder cells; these mimic the thymus environment but have the disadvantage of contaminating the recovered T cells.”
In their research, the group looked at PI3K, the intracellular signal transducer enzymes that interact with T cells as they develop in the thymus and allow the transduction of signals into the cells. They were able to identify the members of the PI3K family that attach to the T-cell surface and thus begin to uncover the function of these signals. For example, PI3K-p110δ transmits signals from the pre-T cell receptor, the precursor of the foreign antigen recognizing T-cell receptor. PI3K-p110γ transmits signals from the chemokine receptor CXCR4, which recognizes the thymically derived chemokine CXCL12 and is also a receptor used by HIV to infect cells.
Traditionally, chemokines are involved in directing cells of the immune system to travel along a gradient towards the site of infection in a process known as chemotaxis. This finding suggests that CXCL12 is also a growth factor for developing T cells.
Janas described the impact that this finding could have: “Producing T cells without additional feeder cells requires a greater understanding of the growth factors normally provided by the thymus. The discovery that CXCL12 is critical for immature T-cell growth brings us a step closer to achieving this goal. We have shown that immature T cells isolated from the thymus could only continue their developmental program when cultured in the presence of CXCL12 and another growth factor known as Notch-ligand. This is the first demonstration of T-cell development in vitro that does not require supporting feeder cells.”
Source: Babraham Institute, Cambridge, UK www.babraham.ac.uk