Immunotherapy targets NHL

Four of 38 patients with non-Hodgkin's lymphoma have seen "complete regressions" following immunotherapy treatment, while five others saw reductions of 50 per cent in their tumours.

The drug works by activating the body's own defences to attack the cancer.

The results have been described as an "exciting" and "significant" development in the use of immunotherapy, the process of using the body's own immune system to fight disease.

Professor Peter Johnson, Cancer Research UK's chief clinician, said: "These exciting preliminary results come from using them to harness the body's own immune response in a new way. Although the side effects need to be monitored carefully, we hope that this type of treatment will prove to be active in larger trials in the future"

"This a significant study," said Dr Cassian Yee, Fred Hutchinson Cancer Research Center, Seattle, who has had significant results using the alternative method of treating patients with white blood cells grown in the lab. "It remains to be seen if most of the responses are longlasting. Certainly the results are very promising."

The drug, which has been developed by Micromet, in Bethesda, Maryland, was trialled by a team led by Dr Ralf Bargou at University of Würzburg in Würzburg, German.

The results, published in the journal Science, are encouraging because they suggest that the bigger the dose, the bigger the effect.
Coauthor of the study Dr Patrick Baeuerle, of Micromet, said all seven who received the highest dose responded to the drug.

"Two of the seven had a complete response, and five a partial regression (greater than 50 per cent reduction of tumour)."

The longest duration of a response was so far seen in a patient who received one quarter of their dose. After 13 months, he remains free of the blood cancer.

There are adverse side effects involved, however, such as fevers and chills, occasionally with confusion and tremor, though all stopped after treatment ceased.

Now a further trial is investigating how the drug works in patients with another form of blood cancer, called acute lymphoblastic leukaemia.

Micromet targets the body's own white blood cells on the cancer, using a fraction of a millionth of a gram of a specialised protein called a "bispecific antibody".

The company has created antibodies, called BiTE antibodies, which are able to stick to sites with exquisite precision, in this case to activate specialized white blood cells (T cells) to attack cancer.

The antibodies overcome a key problem with immunotherapy that as tumours become more advanced they become more "invisible" to the T cells because the cancer cells lack molecules for white blood cells to hang on to and stage their attack.

Normal antibodies are designed to latch on to one molecular target but the bispecific antibody developed by Micromet, given the name blinatumomab, binds to two, the cancer cell and the T cell, and bring the two together to target the immune system on the cancer.

The team tried varying doses of blinatumomab in patients, and found that among 38 patients, at doses from 0.0005 to 0.06 milligrams (millionths of a gram) per square metre of body surface per day, 11 of them exhibited major responses and tumour shrinking. The disease was cleared from bone marrow, spleen and liver too.

MMRC announces clinical trial of pomalidomide CC-4047

Paul Richardson, MD, Clinical Director of the Jerome Lipper Center for Multiple Myeloma at DanaFarber Cancer Institute, is leading the multicenter, randomized, open-label, dose-escalation study. A Phase 1 study is designed to determine maximum tolerated dose of single-agent pomalidomide while a Phase 2 randomized study will compare the oral compound's efficacy alone against its combination with dexamethasone.

"This potent new immunomodulator, which is in the same class as thalidomide and lenalidomide, will hopefully be successful in treating patients who have relapsed or who don't respond to currently available treatment options. We are excited to be testing pomalidomide in this context and are optimistic that it will meaningfully add to our therapeutic options for our patients," said Dr. Richardson.

Pomalidomide is an IMiDs compound, a member of Celgene's proprietary group of novel oral immunomodulatory agents that impede or stabilize disease through several mechanisms of action, including anti-angiogenic activity.

Celgene's lead IMiDs compound, REVLIMID (lenalidomide) continues to demonstrate unprecedented overall survival in multiple myeloma as well as significant clinical potential across a broad range of blood cancers.

IMiDs compounds are proprietary novel small molecule, orally available compounds that modulate the immune system and other biologically important targets through multiple mechanisms of action, including angiogenesis inhibition, modulation of the levels of key pro-inflammatory and regulatory cytokines and immune cell co-stimulation.

Proteolix Initiates Phase 1b Clinical Trial of Carfilzomib

Patient dosing has commenced in a Phase 1b clinical trial to evaluate the safety and efficacy of Proteolix's lead anti-cancer agent, carfilzomib (PR-171), in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma. Carfilzomib selectively blocks proteasome activity, causing apoptosis in cancer cells. In single agent Phase 1 studies carfilzomib has demonstrated encouraging anti-tumor activity and has been generally well tolerated.

The Phase 1b clinical trial is designed to evaluate safety and to establish a maximum-tolerated dose of carfilzomib in combination with lenalidomide and dexamethasone on a twenty-eight day treatment cycle. Lenalidomide in combination with dexamethasone is indicated for use in patients with multiple myeloma who have had at least one prior therapy. Patients will be divided into four cohorts and will receive escalating doses of carfilzomib and lenalidomide, combined with a set dose of dexamethasone. A secondary endpoint for the trial is overall response rate at four months.

"Carfilzomib has been generally well-tolerated in patients and we believe that the product's selectivity and potency provide a solid rationale for use in combination with existing treatment protocols," said Lori Kunkel, M.D., Proteolix's Chief Medical Officer. "Initiating our first combination trial of carfilzomib complements our multi-pronged strategy to thoroughly explore carfilzomib's potential in the treatment of patients with multiple myeloma for whom treatment options may be limited."

In addition to the Phase 1b clinical trial announced today, Proteolix is currently evaluating carfilzomib as a single agent for the treatment of multiple myeloma in two Phase 2 clinical trials.

A Phase 2 clinical trial of single-agent carfilzomib in patients with relapsed and refractory multiple myeloma recently began enrolling its second cohort of approximately 40 patients to explore safety, tolerability and activity using a higher dose schedule. This trial is being conducted in collaboration with the Multiple Myeloma Research Consortium (MMRC) and is designed to evaluate patients' overall response rate after four cycles of carfilzomib. All patients enrolled in the trial have received prior treatment(s) with bortezomib and either lenalidomide or thalidomide and are refractory to their last treatment.

A second open-label, multi-center Phase 2 trial of single-agent carfilzomib in relapsed multiple myeloma patients is also currently enrolling patients. The goal of this study is to evaluate carfilzomib's activity based on a patient's prior treatment with bortezomib. The company plans to present interim data from both of these Phase 2 trials by year end. A complete list of Proteolix's ongoing clinical trials of carfilzomib may be found at http://www.clinicaltrials.gov.

About Carfilzomib

Carfilzomib is a structurally- and mechanistically-novel proteasome inhibitor that exhibits a high level of selectivity for a single active site in the proteasome with minimal cross reactivity to other protease classes.

Bristol-Myers Squibb and PDL BioPharma Alliance to Develop Novel Treatment for Multiple Myeloma

Bristol-Myers Squibb Company (NYSE: BMY) and PDL BioPharma, Inc. (NASDAQ: PDLI) today announced an agreement for the global development and commercialization of PDL BioPharma's anti-CS1 antibody, elotuzumab, previously known as HuLuc63, currently in Phase I development for multiple myeloma.

Elotuzumab provides a novel approach to treating multiple myeloma because it is an antibody that binds to the CS1 glycoprotein, allowing the immune system to selectively kill myeloma cells with minimal effects on other cell types. CS1 is a cell surface glycoprotein that is widely expressed on multiple myeloma cells but is minimally expressed on normal cells. Elotuzumab is currently being investigated in Phase I studies as a monotherapy and in combination with other therapies. There are currently no approved monoclonal antibodies on the market to treat multiple myeloma.

"Elotuzumab provides us with the opportunity to develop and market an innovative therapy that has the potential to meaningfully address the significant unmet medical need in multiple myeloma," said Francis Cuss, MD, senior vice president, Discovery and Exploratory Clinical Research, Bristol-Myers Squibb.

Review of new drugs in multiple myeloma

Berenson JR, Yellin O.

PURPOSE OF REVIEW: Advances in the understanding of multiple myeloma pathogenesis have led to the development of innovative targeted therapies and improved management of this aggressive hematological neoplasia. This review will focus on the clinical trials that have reinforced the use of these new agents. Also, we will briefly take a look at the newer drugs making their way out of the laboratory and into early phase studies.

RECENT FINDINGS: During the past decade new multiple myeloma therapies featuring bortezomib and lenalidomide have come to light, whereas known agents such as thalidomide and arsenic trioxide have been reintroduced as key factors in multiple myeloma management. These new agents and their combinations have shown increased response rates and have added more options for patients with multiple myeloma whose disease has become resistant to conventional therapy. With these drug therapies has come a more targeted approach to treatment enabling not only improved antimyeloma efficacy but also the use of decreased dosing enhancing the safety and tolerability of these regimens. Newer agents including the histone deacetylase, hsp90, mammalian target of rapamycin and Akt inhibitors are showing promise preclinically and are now being assessed in phase I/II trials.

SUMMARY: This new antimultiple myeloma arsenal has shown its worth in both the relapsed/refractory and frontline setting and provides valuable options for patients with this debilitating disease.

PMID: 18685422 [PubMed - in process]

SymBio Pharmaceuticals and Eisai Sign License Agreement for bendamustine hydrochloride (SyB L-0501)

Tokyo – SymBio Pharmaceuticals Limited and Eisai Co., Ltd. announced today that the companies have concluded the license agreement for the co-development and commercialization of bendamustine hydrochloride in Japan.

In Germany, bendamustine hydrochloride has been used extensively for the treatment of non-Hodgkin's lymphoma, multiple myeloma and chronic lymphocytic leukemia. The drug has been on the market in the United States since April of this year after receiving FDA approval in March 2008 for the treatment of chronic lymphocytic leukemia. In Japan, bendamustine hydrochloride is currently being investigated in patients with low-grade non-Hodgkin's lymphoma, and is in the pivotal stage of clinical development prior to submission for approval.

In a collaborative effort to address unmet medical needs, SymBio and Eisai will work in tandem to expedite the development of bendamustine hydrochloride in Japan.

Molecules Out Of Balance Lead to Multiple Myeloma

An international team of scientists has identified processes that are heavily implicated in human multiple myeloma and other B cell cancers.

B cells, the white blood cells that produce antibodies, form a key part of our 'immune response'. To remain healthy, we need to maintain the right number of B cells, not too many and not too few. This in turn relies on an intricate interplay of molecules within our bodies, and inside our B cells.

Professor Fabienne Mackay, Professor Klaus Rajewsky and Dr Marc Schmidt-Supprian, from Sydney's Garvan Institute of Medical Research, Harvard Medical School and Germany's Max Planck Institute of Biochemistry respectively, have identified two processes that appear to influence B cell driven cancers. Their findings are published online in the international journal, Proceedings of the National Academy of Sciences.

"We already know that the over-expression or mutation of molecules known as NIK and TRAF3 in B cells is associated with multiple myeloma," said Professor Mackay. "Our collaborative research uncovered two distinct processes involving these molecules that help explain why."

The first process involves NIK, an enzyme that acts closely with BAFF, the substance that regulates the number of B cells in our bodies. Work done previously by Professor Mackay on BAFF showed that levels correlate with B cell hyperplasia (expansion) and cancer. The current study shows that if we have too much NIK in our systems, then our B cells will also expand, and we will be prone to cancer.

The second process, associated with the first, involves TRAF3, the molecule that negatively regulates NIK.

Professor Mackay explained that in a healthy person, NIK and TRAF3 work together, helping to maintain the right number of B cells for survival. "But when there are mutations in either molecule, they become uncoupled. In other words, TRAF 3 no longer represses the action of NIK when necessary."

"The important thing to note is that when you uncouple NIK from TRAF3 action, its levels are not necessarily going to go up, but its function is going to be changed. This can lead to B cell hyperplasia and cancer."

"Our paper is saying 'be careful'! Sometimes you can find a patient without high expression of NIK, so you think NIK is not implicated, where it might be."

"In the very near future, we will have the capacity to do blood tests and test for specific gene mutations in patients. Once you identify a mutation, you can bypass the action of that gene, with targeted medications."

Bottom of Form

"Both NIK and TRAF3 are molecules, so can potentially be targeted by pharmaceuticals. We anticipate that new treatments for cancers may emerge from our findings."