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Immunotherapeutic Targeting in Children


The backbone of cancer therapy in pediatric oncology has been stepwise integration of multimodality therapies (eg, chemotherapy, surgery, radiation therapy) into carefully designed treatment regimens tested sequentially through multicenter randomized trials. Although chemotherapy has been effective in eradicating micrometastatic disease in some conditions and remains a principal determinant of success, the toxicity associated with current cytotoxics is substantial, and current agents have not proven curative in several clinical groups.

Hence, the need is growing for the development of effective, alternative anticancer therapies for use in children with tumors. Dramatic progress in technology has improved our understanding of the basic biology of tumor immunology, and immune-based therapies represent one approach that could be integrated into current multimodal regimens to eradicate micrometastatic disease.

Immunotherapeutic targeting of cancers is an attractive, novel modality that could be used either in conjunction with conventional therapies or separate from these therapies. Evidence currently suggests that the mechanisms responsible for resistance to cytotoxic agents generally do not confer resistance to immune-mediated mechanisms of tumor-cell killing.

The immune system participates in immunosurveillance of tumors, as evidenced by the following:

Patients develop spontaneous innate and acquired immune responses to their tumors.

One positive prognostic indicator of patient survival in many histologies is infiltration of lymphocytes within a tumor.

Immunosuppressed transplant recipients display higher incidences of nonviral tumors than age-matched immunocompetent controls.

Various murine studies have reported that both spontaneous and carcinogen-induced tumors occur more frequently in mice that lack various elements of innate and adaptive immunity.

Tumors are less able to survive in immunocompetent mice.

This last observation provides evidence that the development of immune-evasive properties occurs in response to immune pressure early during the period of oncogenesis. Merchant and colleagues also suggest that T-cell–depleting cancer therapies may eliminate beneficial immune responses and that immune reconstitution of patients with lymphopenic cancer could prevent metastatic recurrence of solid tumors.

In summary, current models hold that tumor antigens are present and induce immune reactivity during incipient tumor growth and that tumors subsequently develop properties to evade these immune responses. The challenge to the current field is to elucidate the biology of host-tumor interactions at the time of clinical presentation with cancer and to develop approaches that diminish the capacity for tumors to evade immunity and amplify host antitumor immune responses. In pediatric oncology, the ability to apply such therapies during a period of minimal residual disease is compelling and can often be accomplished with modern multimodality therapies.

The immune system consists of multiple levels of defense against invading pathogens. It consists of physical barriers, mechanisms of innate immunity as well as adaptive immunity. The physical barrier can be mechanical, chemical, or biological and located at different sites in the body including skin, secretions within the respiratory tract, and in the gastrointestinal or genitourinary tract as flora. The cells that have the inherent property of innate and adaptive immunity within the body are present at different sites including the blood, lymphatic system (lymph, lymphoid nodules and lymphoid organs), epithelium, and connective tissues. For more information about the relevant anatomy, see Immune System Anatomy.

Current immunotherapies may involve either innate or adaptive (acquired) immunity.

Innate immunity does not induce immunologic memory. It can directly kill tumor cells. This immunity plays a critical role in initiating adaptive immune responses. Innate immunity includes the role of toll-like receptors (TLRs) in improving antitumor and vaccine responses, muramyl tripeptide phosphatidylethanolamine (MTP-PE) in osteosarcoma, and natural killer (NK) cell–killer immunoglobulinlike receptor (KIR) mismatch. This can also augment tumor growth and invasion.

Adaptive immunity induces immunologic memory and can directly kill tumor cells or recruit other effectors through cytokine production. B cells are professional antigen-presenting cells (APCs) that generate antibodies in response to a foreign antigen.

T cells are potent tumor cell killers that recognize peptides derived from the target cell (extracellular or intracellular) but must be presented by major histocompatibility complex (MHC) molecules. Activation of T cells also requires a second signal provided by a costimulatory molecule. T cells used in a donor lymphocyte infusion or as part of a stem cell transplant can have potent graft-versus-leukemia effects.

Vaccines have been designed as a means of providing a targeted tumor antigen with an appropriate costimulatory signal to enhance T-cell responses. Cytokines and growth factors have been used on pediatric tumors as a means of directly killing tumors or improving host antitumor responses but with limited success.

Monoclonal antibodies (mAbs) target only cell surface antigens and can induce antibody-dependent cellular cytotoxicity (ADCC) or complement fixation; they can be directly cytotoxic or serve as targeting agents to deliver lethal “hits.” mAbs have been used as single agents or in combination with chemotherapy and can be conjugated with radioisotopes or toxins to enhance their potency.

Go to Induction of Tolerance for information on this topic.

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