Cancer Drug

Cancer Drug Improves Organ and Stem Cell Transplantation in Large Animals

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Researchers from Harvard Medical School (HMS) and Massachusetts General Hospital (MGH) show that the approved leukemia drug venetoclax helps large animals accept transplanted stem cells and organs, like kidneys. The research team, led by Hajime Sasaki, MD, PhD, and Takayuki Hirose, MD, PhD, demonstrated that selective inhibition of B cell lymphoma 2 (Bcl-2) promoted the tolerance of hematopoietic stem cell (HSC) transplantation and renal allograft in a nonhuman primate model despite using only half of the dose of total body irradiation previously required. Selective inhibition of Bcl-2 is therefore a new strategy to improve stem cell transplants and lessen the toxic effects of conditioning regimens, which are a major obstacle to the widespread use of stem cell transplantation in clinical settings.

“This method (brief inhibition of Bcl-2) makes bone marrow transplantation easier,” senior author Tatsuo Kawai, MD, PhD, told GEN. “The patient does not need to be admitted for bone marrow transplantation, which may expand bone marrow transplantation applications for many benign diseases, such as induction of tolerance for transplant organs.”

The research article “Selective Bcl-2 inhibition promotes hematopoietic chimerism and allograft tolerance without myelosuppression in nonhuman primates” was published in Science Translational Medicine.

HSC transplantation (HSCT) has become the standard of care for both cancerous and noncancerous diseases of the blood and bone marrow, like autoimmune diseases, genetic disorders, and making the body accept a transplant. However, the wider clinical application of HSCT has been limited by the nonselective conditioning therapies associated with this approach.

In order for HSCT to work, the recipient must go through a harsh conditioning process that includes total body irradiation or chemotherapy drugs like cyclophosphamide, busulfan, or fludarabine. These treatments often have serious side effects like a lower-than-normal number of red and white blood cells and platelets in the blood (pancytopenia), infections, infertility, and even death.

Transient HSC chimerism induction has led to long-term immunosuppression-free renal allograft survival in humans, but pancytopenia and other side effects of the HSCT conditioning regimen have kept this method from being used more often. Therefore, developing a safer conditioning regimen without myelosuppressive complications is critically important.

In 2013, research done at the University of Zürich by Pietro E. Cippà and Thomas Fehr (who are both authors of the Science Translational Medicine article) showed that blocking B cell lymphoma 2 (Bcl-2) promotes mixed chimerism in mice without the need for traditional myelosuppressive conditioning. However, this study used a non-clinically available Bcl-2 inhibitor (Bcl-2i), ABT-737, which inhibits not only Bcl-2 but also BclxL.

Since venetoclax, which selectively inhibits Bcl-2 alone, is the only Bcl-2i approved by the  U.S. Food and Drug Administration (FDA), the research team from HMS and MGH evaluated the effect of venetoclax on peripheral lymphocytes and bone marrow progenitors in a non-human primate model and determined its efficacy in inducing mixed chimerism and renal allograft tolerance. The research article shows that Bcl-2i causes dose-dependent cell death in vitro and causes HSCs and multipotent progenitors (MPPs) to be partially deleted in vivo. This partial removal of HSCs and MPPs led to a big increase in hematopoietic chimerism, which made it possible to cut the amount of radiation given to the whole body in half. However, Bcl-2 inhibition by itself was not sufficient to completely eradicate TBI.

Promoting mixed chimerism by Bcl-2i resulted in improved immunosuppression-free renal allograft survival. In the group receiving the original protocol with total body irradiation but without Bcl-2i, one of the eight animals experienced acute rejection, and three of the eight developed chronic rejection, reducing long-term, rejection-free allograft survival to 50%. When the total body irradiation dose was decreased to half, four of the five recipients lost their kidney allografts because of acute rejection. By adding Bcl-2i to the regimen, superior rejection-free allograft survival was consistently achieved with a higher degree of lymphoid chimerism, which has been found to be relevant to allograft tolerance.

This approach not only removes a major hurdle from the wider application of our approach for the induction of renal allograft tolerance but also advances the design of less toxic conditioning regimens that can be used in conjunction with HSCT to treat a wide variety of disorders. 

The US has given fast-track approval to a surprising new cancer drug

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“Even when it’s killing cells, you feel great.”

A new cancer drug called Venetoclax is causing quite a stir in the medical community, with the announcement that the US FDA has given it fast-track approval for the treatment of patients with chronic lymphocytic leukemia (CLL).

CLL is one of the most common types of leukemia in adults, and during a recent clinical trial, 80 percent of patients treated with Venetoclax experienced complete or partial remission of their cancer.

Developed in Australia over several decades, Venetoclax is taken in pill-form, and of the small sample of patients who have been treated with it so far, some reported no adverse side-effects at all.

“It causes no side-effects. Nothing, absolutely nothing,” Robert Oblak, who had recurring CLL when he was selected to participate in the trial in 2013, told the ABC. “Quite amazing. So even when it’s killing cells, you feel great.”

Oblak estimates that he was just the 11th person in the world to be treated with Venetoclax, and within a year of treatment, he went into remission.

The phase II trial involved 107 patients aged 18 or older with CLL, who had undergone at least one type of treatment already.

The patients also had to have a particular chromosome abnormality in their leukemia cells called 17p deletion, which means they’re lacking a portion of the chromosome that acts to suppress cancer growth.

They were asked to take one Venetoclax pill per day for five weeks straight, with doses starting at 20 mg and gradually increasing to 400 mg.

At the end of the trial, which involved patients and researchers from 31 centres in the US, Canada, the UK, Germany, Poland, and Australia, four out of five patients experienced a positive result, with complete remission reported for one in five.

“These patients now have a new, targeted therapy that inhibits a protein involved in keeping tumour cells alive,” Richard Pazdur from the FDA’s Centre for Drug Evaluation and Research, announced back in April. 

“For certain patients with CLL who have not had favourable outcomes with other therapies, Venclexta may provide a new option for their specific condition.”

The results of the trial, which were published in The Lancet in June, informed the FDA’s decision to fast-track approval of the drug and make it available to patients in the US.

Despite being developed by researchers at Australia’s Walter and Eliza Hall Institute of Medical Research, it’s not yet been approved for use by Australian patients, but an application has been made.

So, how does the drug work? Venetoclax is one of a new generation of immunotherapy cancer drugs that are designed to address certain failings of a person’s own immune system – such as missing portions of chromosomes that inhibit the cells’ ability to fight the spread of cancer.

In CLL patients with 17p deletion, malignant cells don’t proliferate all that much, but they don’t die, because the body’s immune response has been hindered, and abundant levels of a protein called BCL2 helps keep them alive.

“Cells, when they are born, are destined to die and cancer cells and particularly leukaemia cells delay that death by using a protein called BCL2 that stops the normal time of death,” John Seymour from the Peter MacCallum Cancer Centre in Melbourne, who helped oversee the trial, told the ABC.

“Venetoclax works by specifically blocking the action of that BCL2, and allows the cells to die in the way that they were destined to.”

venetoclax-actionVenetoclax

So rather than killing off the cancer cells – and a bunch of healthy cells in the vicinity – like current treatments like chemo and radiotherapy do, the drug reestablishes the balance of the body’s immune system, and effectively allows the cancer cells to die on their own.

This explains why some patients, like Oblak can undergo treatment with no discernible side-effects. But let’s be clear – Oblak was very lucky.

The FDA reports that, depending on the patient, side-effects from Venetoclax include low white blood cell count, diarrhoea, nausea, anaemia, upper respiratory tract infection, low platelet count, and fatigue. Serious complications can include pneumonia, fever, and death.

During the Venetoclax trial, of the 107 patients, 11 ended up dying, seven because of the progression of their cancer, and four from adverse side-effects.

Similar results were seen in a separate trial of a similar immunotherapy cancer drug, Ipilimumab, which has recently been approved for the Australian market.

While Australian patient Greg Lawson was declared free from melanomas 12 months after treatment, and reportedly suffered “virtually no side-effects”, his wife, who was treated with a different melanoma immunotherapy drug at the same time, died when her body could not tolerate the treatment.

“She had two sets of the treatment, but was so ill from the side-effects that the decision was made to take her off it,” Lawson told the ABC.

But with immunotherapy drugs seeing “extraordinary” results in other trials this year, and with the possibility of a ‘universal cancer vaccine’ hanging in the air, this is just the beginning for the next generation of cancer treatment.

 

Hepatitis B Infection 100% Eliminated With Cancer Drug Combination In Preclinical Model

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the liver

A new drug trial has promising results for hepatitis B treatment. 

A cancer drug was 100 percent successful in clearing away hepatitis B infections in preclinical models for an Australian study. If researchers successfully replicate the results in human clinical trials, the drug may become the first-ever cure to the hepatitis B virus and may serve as a model for treating other viruses, such as HIV and herpes.

Researchers at the Walter and Eliza Hall Institute in Melbourne, Australia used a combination of the cancer drug birinapant and the antiviral drug entecavir to completely eliminate hepatitis B infections in “hundreds of tests in preclinical models,” lead researcher Dr. Marc Pellegrini explained in a press release. Human trials began in December 2014, and drug testing has currently moved on to a phase 1/2a in clinical trials.

Hepatitis B is a viral infection that attacks the liver. It is transmitted via contact with infected blood or bodily fluids and causes chronic liver infection, which may lead to life-threatening cirrhosis or liver cancer. According to the World Health Organization, there are an estimated 240 million people who are chronically infected with hepatitis B, and around 780,000 people die from complications due to their infection each year.

Although a vaccine against the virus has been available since 1982, treatment of those who are already infected is limited. This is because the virus is able to override the liver’s self-preservation mechanism. Normally, at the sign of infection, the liver will switch on a signal that tells cells to self-destruct in order to prevent further infection, Pelligrini explained. The hepatitis B virus destroys this communications switch and tells the cells to ignore rather than fight the infection. Birinapant is able to reverse this viral override, and restore the liver’s natural infection-fighting defense.

“Birinapant flips the cell survival ‘switch’ used by the virus, causing the infected cell to die,” Pelligrini said.

The team also found that when birinapant was used in combination with entecavir, the infection was cleared twice as fast.

Drug resistance is an ever-present challenge for doctors when it comes to treating viruses. A virus learns to adapt to drugs and then becomes resistant to their defense. However, because the new combination indirectly attacks the virus by changing the way the body responds, this problem will most likely not exist.

“The virus relies on the survival mechanisms of the host, so if it can’t exploit them, it dies. Such a monumental change in the virus’s environment may be too big a hurdle for it to adapt to,” Pelegrini added.

The team believes the unique method in which the drug works could be used to explore effective treatments for other viruses such as HIV, herpes, dengue fever, and even bacterial infections such as tuberculosis.

Pellegrini, Dr. Greg Ebert, and their colleagues at the institute have published their research on the new drug combination in two papers in the online journal Proceedings of the National Academy of Sciences. Patients are being recruited to partake in the clinical trials in hospitals located in Perth and Adelaide, Australia.

Source: Pellegrini M, et al. Proceedings of the National Academy of Sciences. 2015.