The rarity of childhood cancer makes it difficult to develop therapeutic treatment for patients. Small patient populations impact the logistics and execution of clinical trials investigating novel therapies. It appears, however, that the pharmaceutical industry especially experiences a number of challenges in drug development for paediatric cancers. The latest advancements in this area like stem cell therapy show the potential to overcome some of these challenges. 

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The pharmaceutical industry 

Cancer treatment will always be a daunting experience, especially so for children. Paediatric cancer especially presents numerous challenges in drug development. One of the main targets for the pharmaceutical industry is the formulation of oral drugs. Unfortunately, small tablets are not easily tolerated by children, which is why drug companies are continuously designing easier ways of administration. 

A 2015 review highlighted that “small-molecule inhibitors recently developed are highly insoluble, making the development of a liquid formulation for young children difficult”. Developing a liquid formulation however is not a simple process. Further clinical investigations are required to determine the bioavailability of the drug relative to the original solid formulation. Bioavailability refers to “the extent a substance or drug becomes completely available to its intended biological destination”. This particular factor is largely determined by the dosage form, hence why further investigations are needed in the case of a liquid formulation. 

Currently, the majority of childhood cancers are treated with conventional chemotherapy. However, with paediatric patients living longer, late toxicities are becoming problematic. Late effects of treatment are a particular concern for childhood cancer survivors because this can lead to profound, lasting physical and emotional effects. According to cancer.gov, “60% to more than 90% (childhood cancer survivors) develop one or more chronic health conditions.” 

It is obvious from data on this website that pharmaceutical agents are as responsible for late effects as radiotherapy is. Platinum agents like carboplatin have shown to cause peripheral sensory neuropathy later in life for paediatric cancer patients. Peripheral sensory neuropathy is a neurological condition that develops from nerve damage to the extremities such as the hands and feet. While some cases of neuropathy can be cured, more often than not, the nerve damage cannot be recovered and treatment is aimed at managing symptoms.

Clinical research 

In comparison to adult cancers, paediatric cancers are relatively rare. Unfortunately, the smaller disease population introduces substantial logistical challenges in designing and executing these trials, including patient recruitment. Furthermore, environmental exposures such as toxic chemicals may play a role in childhood cancers. However, they are difficult to identify partly because childhood cancer is so rare but also it is difficult to determine what children might have been exposed to early in their development. This introduces confounding factors in paediatric oncology, where differing developmental environments could impact the efficacy of treatment in patients.  

Another problem is the limited knowledge about cancer biology in children. Due to ethical considerations and psychological vulnerability, it is often difficult to access tissue samples of paediatric cancer. Therefore, a majority of the time, adult cancer treatment is tested on paediatric patients. These clinical trials have not always been successful for a number of reasons. Gene therapy is not often successful in children as childhood cancers have “relatively few genetic alterations, and they often lack the genetic targets for treatments that have been developed and approved for cancers occurring in adults“.

Stem cell therapy: Challenges with paediatric patients

Stem cells are an important part of growth and repair within the human body. They can be defined as a population of undifferentiated cells capable of indefinite self-renewal and can generate many types of highly specialised cells. It is important to understand there are many types of stem cells with different proliferative properties and functions depending on their location or tissue compartment. Hematopoietic stem cells are classified by their ability to self-renew and differentiate into mature blood cells. 

Haemopoietic stem cell transplantation (HSCT) is a type of stem cell therapy via a bone marrow transplant. HSCs for transplantation can be collected from bone marrow (BM) or peripheral blood. Patients with aggressive tumours often receive very high doses of chemotherapy which can cause severe depletion of their bone marrow. This destroys the stem cells which differentiate into blood-forming cells and leukocytes (white blood cells). 

As a result, HSCT has been primarily used as a standard procedure for “the treatment of multiple myeloma, leukemia, and lymphomas after rounds of high-dose radiotherapy or chemotherapy”. Ensuring the levels of HSCs remain sufficient is an important part of the patient’s survival as these stem cells are ultimately responsible for the constant renewal of blood each day. 

HSCT has been used in paediatric cancer patient but is greatly dependent upon the type and progression of disease. In chronic myeloid leukaemia, “the only treatment method which has been proved to be curative is stem cell transplantation”.  Bone marrow transplantation, especially in the early stages of the disease, “is recommended in patients intra-familial or non-relative donors who show full HLA compatibility”. HLA refers to human leukocyte antigens which enable tissue compatibility between the patient and donor. This is an important step for successful transplantation. 

In the case of acute lymphoblastic leukemia, HSCT is limited to very high risk patients in the first complete remission. According to the American Cancer society, it is important that the leukemia is in remission before getting a stem cell transplant. Otherwise, the leukemia is more likely to return.

Autologous stem cell transplants use healthy blood stem cells from the patient to replace damaged bone marrow, whereas allogeneic transplants use donor stem cells to treat cancer/blood cell conditions after high-intensity chemotherapy. 

Stem cell therapy is a complex treatment that can cause life-threatening side effects. This is why the decision to begin stem cell therapy in paediatric patients is a lengthy process. In the case of allogeneic transplantation, the patient’s own bone marrow is destroyed before the transplant can take place. This effectively destroys their immune system which exposes them to a common infection which could prove fatal. 

One of the most common long-term side effects of the high-dose chemotherapy and radiation is infertility. Graft Versus Host Disease is another risk in which the body rejects the transplant, identifying it as foreign body and a threat to the immune system which must be destroyed. 

It is important to note, that while stem cell therapy is a high risk treatment option for children, research is ongoing in other therapeutic areas. Immunotherapy is an emerging option for paediatric cancer patients, while chemotherapy continues to be the most effective option so far. More research is needed to understand the physiological and genetic differences between paediatric and adult cancers that may result in variable clinical responses. Furthermore, novel treatments for paediatric patients are an unmet clinical need, as many of the current treatment options for childhood cancers are developed from the data from adult cancer treatment.

To discuss these topics further with sector experts, and to ensure you remain up-to-date on the latest in clinical development, sign up for Proventa International’s Oncology Strategy Meeting, set for 17 June 2021.

Charlotte Di Salvo, Junior Medical Writer
Proventa International