The Possibilities of Immunotherapy for Children with Primary Immunodeficiencies Associated with Cancers

Abstract

Many primary immunodeficiencies (PIDs) are recognised as being associated with malignancies, particularly lymphoid malignancies, which represent the highest proportion of cancers occurring in conjunction with this underlying condition. When patients present with genetic errors of immunity, clinicians must often reflect on whether to manage antitumoral treatment conventionally or to take a more personalised approach, considering possible existing comorbidities and the underlying status of immunodeficiency. Recent advances in antitumoral immunotherapies, such as monoclonal antibodies, antigen-specific adoptive cell therapies or compounds with targeted effects, potentially offer significant opportunities for optimising treatment for those patients, especially with lymphoid malignancies. In cases involving PIDs, variable oncogenic mechanisms exist, and opportunities for antitumoral immunotherapies can be considered accordingly. In cases involving a DNA repair defect or genetic instability, monoclonal antibodies can be proposed instead of chemotherapy to avoid severe toxicity. Malignancies secondary to uncontrolled virus-driven proliferation or the loss of antitumoral immunosurveillance may benefit from antivirus cell therapies or allogeneic stem cell transplantation in order to restore the immune antitumoral caretaker function. A subset of PIDs is caused by gene defects affecting targetable signalling pathways directly involved in the oncogenic process, such as the constitutive activation of phosphoinositol 3-kinase/protein kinase B (PI3K/AKT) in activated phosphoinositide 3-kinase delta syndrome (APDS), which can be settled with PI3K/AKT inhibitors. Therefore, immunotherapy provides clinicians with interesting antitumoral therapeutic weapons to treat malignancies when there is an underlying PID.

Diagnostic and therapeutic approach to children with Nijmegen breakage syndrome in relation to development of lymphoid malignancies

“…Therapeutic approach should be considered in relation to the nature of the NBS as a DNA repair disorder, and to the remaining immune function available in the patient's body, which is required to enhance immunotherapy. Antitumoural targeted therapies, such as monoclonal antibodies (mAb), chimeric antigen receptor (CAR) T-cells and small-molecule inhibitors, potentially offer significant opportunities for optimizing treatment of lymphoid malignancies [45,46].…”

“…The next group are inhibitors of PI3K/ AKT/mTOR pathway, such as sirolimus. In EBV-driven lymphoid malignancies anti-EBV cytotoxic T-lymphocytes are considered as a salvage therapy in refractory disease [45]. There are reported cases that therapy was well tolerated in patients with ataxia telangiectasia [48].…”

“…Therapies that target cell surface antigens are currently undergoing clinical trials with most common indication for refractory/relapse lymphoid malignancy [46]. Agents that may potentially be used in the treatment of patients with NBS and lymphoid malignances are listed in Table 3 [45,46,47]. There are no supportive data on the use of inhibitors of the PI3K/ AKT/mTOR pathway in patients with DNA repair defects [45].…”

Recent Advances in Cancer Immunotherapy

“…The authors comprehensively reviewed the roles of immunosuppressive cells, such as tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T cells, and tumor-associated neutrophils in the development and maintenance of melanoma and non-melanoma skin cancers. The third study is a review paper written by Baleydier et al, which summarized a difficult but interesting issue: cancer immunotherapies for children with cancer with primary immunodeficiencies [ 7 ]. First, the authors summarized the list of primary immunodeficiencies prone to cancer (lymphoma or other hematological malignancies in most of the cases) and their corresponding gene defects (see Table 1 in their review) [ 7 ].…”

“…The third study is a review paper written by Baleydier et al, which summarized a difficult but interesting issue: cancer immunotherapies for children with cancer with primary immunodeficiencies [ 7 ]. First, the authors summarized the list of primary immunodeficiencies prone to cancer (lymphoma or other hematological malignancies in most of the cases) and their corresponding gene defects (see Table 1 in their review) [ 7 ]. The authors then described the molecular mechanisms of immune deficiencies in each syndrome and the oncogenic mechanisms involved in tumorigenesis in children with primary immunodeficiencies.…”