How Can Immunotherapy Be Used in Pediatric Cancer?

Immune therapy in cancer treatement involves stimulating the body's own immune system to attack cancer cells. This approach can be preferable in children with cancer who are less able to tolerate severe side effects of some chemotherapy and radiation regimens.

The immune system is a network of cells and proteins that protects the body from infections and diseases. A healthy immune system attacks and destroys organisms and toxins in the body it doesn’t recognize as its own.

Most immune cells are produced in the bone marrow as stem cells and mature into different types of white cells (leukocytes) such as:

• Lymphocytes (B-cells and T-cells)
• Neutrophils
• Monocytes (macrophages and dendritic cells)

The immune cells circulate in the blood and the lymphatic system. Each kind of immune cell carries out specific tasks in fighting a pathogen. Immune cells release proteins (cytokines) and enzymes to activate other types of immune cells, and also develop antibodies to eliminate foreign organisms.

Neutrophils and monocytes are known as phagocytes because they engulf (phagocytosis) foreign particles and dying cells. The complement cascade is a part of the immune system which enhances the ability of antibodies and phagocytes to attack and remove pathogens.

Humans have three types of immunity:

• Innate immunity: First-line general immunity that protects the body by recognizing pathogens by a general pattern and destroying them.
• Adaptive (acquired) immunity: Immunity that develops after exposure to an antigen from an infection or a vaccination. The immune system remembers and recognizes the specific antigens it has encountered, and develops antibodies against them. Adaptive immunity works in two ways:
• Cellular: T-cells activate and directly attack the antigens.
• Humoral: B-cells activate and produce antibodies which bind to the antigens and destroy them.
• Passive immunity: Temporary immunity, as in the case of a baby, who is protected by the mother’s antibodies through the placenta as a fetus and through breast milk after birth.

Immunotherapy is a form of treatment that involves using the body’s natural immune system to treat a condition. Immunotherapy may take the form of:

• Immunity suppression in conditions such as an autoimmune disease or to prevent organ rejection after a transplant.
• Immunity stimulation to treat certain diseases such as cancers.

The mainstay of pediatric cancer therapy has been an integration of several therapies such as:

• Chemotherapy
• Surgery
• Radiation

The toxicity and side effects of these therapies led to exploration into immunotherapy as a treatment modality. Studies indicate that the immune system plays a role in controlling tumors, and boosting specific parts of the immune system may help in fighting tumor growth and metastasis.

Current evidence suggests that tumors have antigens that evoke an immune response in the early stages of their growth, but the tumor’s cancer cells subsequently develop properties to evade these immune responses.

The targets of immunotherapeutic research are to develop treatments that can

• Diminish the tumor’s capacity to evade immune response.
• Boost the antitumor immune response.

Immunotherapy for pediatric cancer involves methodologies that include:

• Activation of innate immune system
• Activation of acquired immune system
• Cytokine and growth factor therapy
• Monoclonal antibody therapy

Dr. William Coley, who is considered the father of cancer immunotherapy, was the first to notice spontaneous tumor remission in certain sarcoma patients who developed bacterial infections. Dr. Coley pioneered the use of bacterial extractions, named ‘Coley toxins,’ which evoked antitumor immune response in some of his cancer patients.

Immunotherapy was eventually abandoned in favor of radiotherapy because of difficulty in standardizing the toxins. Newer knowledge now shows bacteria are potent in activating the innate immune system, which attacks the tumor cells as well.

The different methods of activating the innate immune system which are in various stages of research currently include:

Toll-like receptor activation

Toll-like receptors (TLR) are proteins in the membranes of immune cells, which recognize molecular patterns generally shared by pathogens, and activate the phagocytes. Toll-like receptors are activated by proteins in pathogens as well as proteins exposed by damaged self-tissue.

Many TLR-targeted therapies for adult cancer treatment are in clinical trials and two therapies have been effectively used:

• Bacillus Calmette-Guerin cell-wall skeleton (BCG-CWS): FDA-approved tuberculosis vaccine and has been used off-label for treatment of early stage bladder cancer.
• Imiquimod: FDA-approved for treatment of basal cell cancer.

Human papilloma virus (HPV) vaccine

HPV vaccine is a TLR-activator (agonist) that has FDA approval for use in children to prevent secondary cervical cancer. Animal studies have shown positive response to TLR-targeted therapies in pediatric cancers that include:

• Acute myelogenous leukemia
• Lymphoma
• Neuroblastoma
• Rhabdomyosarcoma
• Radiation therapy

Research indicates that proteins released from cancer cells damaged by radiation therapy activate TLRs and immune response, and contribute to treatment efficacy.

Alarmins (danger signals)

Alarmins are inflammatory substances released when tumor cells die, which induce an innate immune response. Pediatric tumors such as rhabdomyosarcoma may under-express alarmins to avoid detection by the immune system. Enhancing the innate immune system resulting in better detection of alarmins is a target for immunotherapy research.

Muramyl tripeptide phosphatidylethanolamine (MTP-PE)

Muramyl tripeptide phosphatidylethanolamine (MTP-PE) is derived from muramyl dipeptide, which is a protein fragment found in cell walls of mycobacteria. MTP-PE activates the innate immune system.

Clinical trials of MTP-PE intravenous infusion along with chemotherapy in children with osteosarcoma, have shown improved survival rate. MTP-PE is not FDA-approved for osteosarcoma.

Natural killer cell activation

Natural killer (NK) cells are lymphocytes that are part of the innate immune system. They can identify and kill tumor cells directly, even in the absence of inflammatory signals. The activity of NK cells is regulated by killer immunoglobulin-like receptors (KIR) present in the cells. KIR in tissue native to the body inhibits NK cell activity, but KIR found in foreign tissue activates NK cells.

NK cells can be used to kill the tumor cells with an NK cell-KIR mismatched bone marrow transplant. Clinical trials are ongoing in both children and adult patients for treatment of acute myeloid leukemia, with NK cell-KIR mismatched bone marrow transplant, after self T-cell depletion.

Although activation of innate immune system can have antitumor effects, it can also contribute to cancer growth. Intrinsic conflicts in the immune system complicate the use of innate immunity activation as immunotherapy, because chronic immune inflammation can cause cancer, while anti-inflammatory therapy prevents it.

M1 versus M2 macrophages

Macrophages, which are activated with immunotherapy, are of two types:

• Proinflammatory M1
• Anti-inflammatory M2

Studies show that M2 macrophages contribute to immunosuppression within the tumor and promote tumor progression. The M2 macrophages have been predominantly found in pediatric solid tumors.

Type I versus type II natural killer cells

The two types of natural killer cells are not very clearly understood. Type I appears to activate immune response and antitumor activity, but type II appears to lack a certain receptor that type I has, and may be immunosuppressive.

Myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSC) are a kind of immature myeloid cells which accumulate in tumors and have the ability to suppress both innate and acquired immune systems. Studies are ongoing to develop therapies that inhibit MDSC activity.

The adaptive immune system consists of T-cells and B-cells, which are activated when they recognize a foreign antigen from memory (that is, previous exposure to the substance). T-cells can recognize a foreign antigen only when the receive the following two signals:

The self-major histocompatibility complex (MHC) molecules present the antigen as a fragment of protein (peptide) on the cell surface. MHC is the system by which peptides on the body’s cell surfaces signal whether they are a native cell or foreign organism in the body.

Dendritic cells in the immune system, known as professional antigen presenting cells (APCs) present a molecule and co-stimulate the T-cell to act against the antigen presented by the MHC molecules.

Once activated T-cells directly kill the foreign antigen, and also release cytokines which activate other components of the immune system. B-cells function as antigen presenting cells, besides producing antibodies to the foreign antigen.

T-cell-based therapies

Graft versus leukemia with bone marrow transplant: Bone marrow transplant was initially developed for patients whose bone marrow stopped functioning due to intensive chemotherapy or radiation for leukemia. Clinical experience now shows evidence that the immune response from donor T-cells from the bone marrow transplant may also contribute to prevention of cancer relapse and metastasis.

Current bone marrow transplant therapies are evolving towards enhancing the immune-based effects and reducing radiation and chemotherapy, which can be toxic to the immune system.

Tumor vaccines

Tumor vaccines are prepared with the specific tumor antigens and adjuvants, which are substances that enhance immune response. The tumor vaccine causes an anti-tumor immune response and creation of antibodies which recognize and attack the tumor cells present in the body.

Many vaccines are in clinical trials, but the only one approved by FDA as of 2020 was sipuleucel-T (Provenge) for asymptomatic, metastatic, hormone-refractory prostate cancer.

The challenges with the development of pediatric immunotherapy include the following:

• The rarity of pediatric tumors makes the development and effective testing of vaccines difficult.
• T-cell based immunotherapy is more effective in patients who have low T-cell levels (lymphopenia) after chemotherapy.

Cytokines are proteins released by immune cells which send inflammatory signals to other immune cells. Growth factor is a substance in the body that stimulates cell growth and promotes wound healing. Cytokines and growth factors can be used in two ways:

• As adjuvants to boost the activity of antigen-presenting cells, and augment T-cell activity.
• Suppression of cytokines which reduce the immune response to tumor cells.

Interferon alfa has FDA approval as an adjuvant therapy in several adult cancers which are rare in children. Use of interferon alfa in certain pediatric cancers is still in clinical trials.

Monoclonal antibodies are protein molecules produced in the laboratory. They “recognize” cancer cells, bind to them and activate the immune system. The effectiveness of the monoclonal antibody therapy depends on factors that include:

• The ability of the antibodies to bind only to the tumor cells
• After binding, the antibodies are not shed by the tumor cells

The monoclonal antibodies are foreign proteins and may evoke the immune system to counter them with its own antibodies, neutralizing the monoclonal ones before they can serve their purpose

The monoclonal antibody therapy works in four ways:

• The introduced antibodies directly kill the tumor cells
• The antibodies bind to the tumor cells and attract other white cells that kill them

The monoclonal antibodies are conjugated with a substance that can kill the tumor cell, such as:

• An immunotoxin
• A radionuclide

The patient’s T-cell is genetically modified using a monoclonal antibody to kill the cancer cell

Most of the monoclonal antibody therapies for pediatric cancer are in clinical trials. 

Chimeric antigen receptor (CAR) T-cell therapy

CAR T-cell therapy enhances the patient’s immune system’s anti-tumor activity by genetically modifying their own T-cells. CAR T-cell therapy involves the following steps:

• Extract a sample of the patient’s T-cells.
• Genetically modify the T-cells by fusing them with a substance  specific to the cancer under treatment.
• The fusion results in the T-cells producing structures called chimeric antigen receptors (CAR) on the cell surface.
• The modified T-cells are multiplied in the laboratory.
• The CAR T-cells are infused into the patient.

Tisagenlecleucel (Kymriah)

FDA has approved tisagenlecleucel for children and young adults with acute lymphoblastic leukemia who haven’t responded to other treatments.