IMMUNE THERAPIES TO LESSEN CHEMO BURDEN AND INCREASE CURE RATES

July 5, 2019 0 By S Harachand

Even as chemotherapy and radiotherapy remain the main modes of treating cancer, an increased understanding of the underlying biology has helped to make real progress with new drugs.

A large number of new oncology treatments have been approved for adults over the last few years.

Immunotherapy, for example, is completely changing the landscape. It demonstrates activity across different cancers and offers promise in patients with advanced disease.

PD-1 and PD-L1 antibodies or checkpoint inhibitors work in a wide range of adult tumours. But the question whether these ‘wonder drugs’ might repeat the same magic in paediatric cancers remains.

Cancers affecting children are biologically different from adult tumours and they have a much lower rate of mutations. Historically, the treatment of children with cancer has been shaped by off-label use of adult drugs.

Some of the targets for cancer drugs in adults do not exist in children. However, there are targets in adult cancers that are also relevant in children. For example, B-RAF, which is the target in B-RAF-mutated melanoma, is also mutated in some rare paediatric gliomas.

 

 

“There are some adult tumours that are very responsive to checkpoint inhibitors that also occur in children, like Hodgkin lymphoma. In these cases, it’s natural to translate adult data into children,” says Dr Alix E Seif, Attending Physician, Cellular Therapy & Transplantation Section, Division of Oncology, Children’s Hospital of Philadelphia, USA.

Again, certain cancers, including acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML), osteosarcoma and Ewing’s sarcoma, are the same in adults and children.

The ALK mutation present in some adult lung cancers is also present in some paediatric anaplastic large cell lymphoma (ALCL), neuroblastoma and inflammatory myofibroblastic tumours (IMT). The B-RAF mutation present in some adult melanomas can also be seen in some paediatric ganglioma and histocytosis.

According to Dr Alix, paediatric tumours tend to have far fewer genetic changes, resulting in fewer possible new proteins that can be recognized as abnormal by the immune system. In addition, some children are born with the cancer or with precancerous cells, and their immune systems developed in this setting of abnormal gene products.

In contrast, adult tumours develop after decades of accumulating small changes to the DNA. These changes can be translated into proteins that a “revved up” immune system can recognize as abnormal and attack – this is a contributor to the huge success of checkpoint inhibitors and other immune stimulants for melanoma, for example.

For children, it’s possible that checkpoint inhibitors may help other immune therapies, like CAR T cells, to be more effective or last longer. It’s also possible that checkpoint inhibitors could be combined with other immune stimulants to help overcome the low number of genetic changes in childhood tumours, says Dr Alix.

These pathways are often referred to as immune checkpoints. Many cancers use these pathways to escape the immune system. The immune system responds to the cancer by blocking these pathways with specific antibodies called immune checkpoint inhibitors.

These treatments harness that ability to overcome or enhance more traditional treatments like chemotherapy or radiation, notes Dr Alix. Children who have cancer that comes back or doesn’t respond to standard treatments are resistant to those treatments. Simply giving more of these standard treatments can add to the toxicity without providing any benefit when there are resistant cancer cells.

However, drugs that target signalling pathways that are active in some adult cancers might be difficult to use in children. This is because of the fact that many of these signalling pathways are essential for normal development.

A handful of immunotherapies are currently approved to treat paediatric cancers.

 

Ipilimumab

Ipilimumab (Yervoy), a checkpoint inhibitor that targets the CTLA-4 pathway, is approved for subsets of paediatric patients with advanced melanoma.

Pembrolizumab

Pembrolizumab (Keytruda) is another checkpoint inhibitor that targets the PD-1 pathway. The drug is approved for subsets of paediatric patients with classical Hodgkin lymphoma.

 

Targeted antibodies

Some specific paediatric targets such as the disialoganglioside GD2 in neuroblastoma, which is an exquisitely specific target, are now being investigated with an agent designed to target it.

Dinutuximab

Dinutuximab (Unituxin) is a monoclonal antibody that targets GD2. This molecule, a ganglioside, is expressed on the surface of neuroblastoma cells. The binding of dinutuximab to GD2 initiates an immune response that can kill the cells. It is approved for subsets of paediatric patients with neuroblastoma, the most common solid tumour cancer in childhood, which affects immature nerve cells.

The FDA approval covers the use of dinutuximab after a first-line multiagent, multimodality therapy for patients who have at least a partial response to this initial treatment.

Monoclonal antibodies for neuroblastoma and bispecific antibodies for leukaemia have induced significant clinical responses for chemorefractory patients.

 

CAR T-cell therapy

Cell and gene therapy approaches have also made a great impact in the treatment of paediatric cancers.

 

Tisagenlecleucel

A CAR T-cell treatment, tisagenlecleucel (Kymriah), was approved by the US FDA for certain paediatric patients with a form of ALL that is in a second or later relapse. Each dose of the CAR T-cell treatment is created using the patient’s own immune T cells, which are genetically modified in a laboratory to target leukaemia cells. The modified cells are then returned to the patient to kill the cancer cells.

Several immunotherapies are also under evaluation in different phases of clinical trials.

“Immunotherapy is blossoming, and there are many, many trials opening around the world,” comments Dr Alix. “Many are capitalizing on the success of CAR T cells – looking at targeting more than one target at once or new targets for leukaemias and solid tumours.”

There are early-phase studies of checkpoint inhibitors for solid tumours, including those that combine them with other immunotherapies (blinatumomab) for ALL. The next wave of studies will try immune therapies earlier in treatment to see if we can achieve even better outcomes for children with hard-to-treat leukaemias, she adds.

DRUGS IN PIPELINE

Selumetinib

Selumetinib is an MEK inhibitor in paediatric patients with recurrent or refractory low-grade glioma.

Additionally, the Paediatric Brain Tumor Consortium (PBTC) studied the targeted agent in children with relapsed or refractory low-grade gliomas. Reductions in tumour size were observed in most patients. Based on these results, Children’s Oncology Group (COG) will be studying the drug in phase 3 clinical trials for children with newly diagnosed low-grade glioma.

The US FDA has recently granted Breakthrough Therapy Designation to selumetinib for the treatment of paediatric patients with neurofibromatosis type 1 (NF1) symptomatic and progressive, inoperable plexiform neurofibromas (PN), a rare, incurable genetic condition.

 

ONC201

ONC201 is a water soluble, orally bioavailable inhibitor of the serine/threonine protein kinase Akt (protein kinase B) and extracellular signal-regulated kinase (ERK), with potential antineoplastic activity. The Akt/ERK inhibitor binds to and blocks their activity, which may result in the inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction pathway as well as the mitogen-activated protein kinase (MAPK)/ERK-mediated pathway.

A multicentre, open-label, five arm, dose escalation, phase I study of oral ONC201 in paediatric patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG) and recurrent / refractory H3 K27M gliomas.