What are the limitations of adaptive immune system activation in immunotherapeutic targeting in pediatric oncology?

Updated: Mar 20, 2018
  • Author: Crystal L Mackall, MD; Chief Editor: Jennifer Reikes Willert, MD  more...
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Answer

Various challenges face the development of immune-based therapies for childhood cancer. One challenge to the development of vaccines for pediatric tumors is the rarity of these tumors; hence, effective testing of vaccine strategies directed at common immunodominant antigens is difficult.

Although identification of a particular peptide that is capable of inducing antitumor effects may be possible in patients with a given major histocompatibility complex (MHC) and pediatric tumor, this is likely to occur in only a few patients per year. Thus, the ability to test such complicated and specific therapies in rare tumors is limited, and the clinical applicability of using specific targeted epitopes is small.

Hence, enthusiasm is greater for targeting more public tumor antigens that are shared across different tumor types and for developing immunizing approaches that can be used across human leukocyte antigen (HLA) types, such as whole-protein or whole-cell techniques.

A second challenge is that because dose-intensive chemotherapy is a standard component of almost all therapies for pediatric tumors, integrating T-cell–based therapies into existing therapies requires attention to the important changes in T-cell homeostasis induced by lymphopenia, which impacts the effectiveness of T-cell–based immunotherapy.

Although pediatric patients have more rapid recovery of immunity after T-cell–depleting chemotherapy than adults do, they still usually need at least 6-12 months to achieve immune recovery after dose-intensive chemotherapy. [70, 71, 72, 73, 74, 75]

Recent studies have demonstrated that lymphopenia can provide a fertile milieu for immunotherapy; however, this is not universally true. In general, lymphopenic hosts appear to provide a reasonably fertile environment for adoptive immunotherapy. Immunization undertaken in the context of lymphopenia can be more effective than when undertaken in T-cell–replete hosts if adequate T-cell numbers and effective antigen-presenting cells (APCs) are provided. [76]

Results of a study of patients with Ewing sarcoma and alveolar rhabdomyosarcoma were recently reported. Adoptive T-cell transfer was administered, with peptide-pulsed dendritic cell (DC) vaccines undertaken during the period of lymphopenia that immediately followed dose-intensive chemotherapy, and the overall survival for patients with metastatic or recurrent Ewing sarcoma or alveolar rhabdomyosarcoma treated with adoptive T-cell transfer and DC vaccination was 43% at 5 years. [74]

Interestingly, although the patients showed minimal measurable immune responses to the peptide-based vaccine, which targeted the translocation breakpoint junctions, they were immunocompetent to influenza vaccination within 3 months following completion of chemotherapy.

A third challenge is that the optimal technique for tumor vaccination has not been defined. Peptide-based vaccines have been successfully used by some groups and are known to be simple to produce, relatively inexpensive, and safe. [77] However, as noted (see above), such an approach requires identification of a tumor-specific or tumor-associated peptide, which is challenging because of the rarity of pediatric tumors.

For neuroblastoma, peptides derived from the amplification of the MYCN oncogene have been shown to be capable of inducing immune responses ex vivo and capable of lysing neuroblastoma cells in patients with HLA A1+ tumors; thus, this target could potentially be clinically exploited in future studies. [78] Peptide-based DC vaccines were developed to target the translocation breakpoints in Ewing sarcoma and alveolar rhabdomyosarcoma, but no clinical responses were observed. [79]

WT1 is a zinc finger transcription factor that is overexpressed in various hematologic and solid tumors, and peptide vaccines that express WT1 have yielded clinical responses in various adult malignancies. [80] It has recently been found to be a target antigen for the graft-versus-leukemia effect. [81] Trials are now underway using vaccines that express WT1 in children (see Clinicaltrials.gov).

An alternative approach is to use components of the tumor cells themselves to potentially immunize patients of any HLA type to various potential antigens available within the tumor. For example, Geiger et al used tumor lysate–pulsed DCs to immunize patients with pediatric solid tumors and reported some preliminary evidence for antitumor effects. [82, 61]

Neuroblastoma cells have also been transduced using complementary DNA-encoding cytokines and have been subsequently used to immunize patients. [83, 84] The rationale for this approach is based on data demonstrating that stimulatory cytokines can generate immune responses that show cytolytic activity for both cytokine-secreting and non–cytokine-secreting cells that bear the same antigens.

Clinical evidence for antitumor activity was obtained by using autologous neuroblastoma cells transduced to secrete interleukin (IL)-2, which resulted in a 20% objective tumor response and a 30% stable disease rate in 10 patients. [85] As a result of the technical difficulties of reliably generating gene-transfected tumors in patients, these investigators have also explored the use of allogeneic neuroblastoma cells transduced with IL-2. [83] Neither treatment produced any toxicity aside from local induration at the site of tumor injection.

Repeat studies attempted to improve the outcome of this approach by cotransfecting the complementary DNA–encoding cytokines with the chemokine lymphotactin in autologous neuroblastoma cells; a few complete and partial responses were noted in one trial, but no responses were noted in the other. [86, 87]

The potential of using master cell banks of allogeneic tumors as immunogens is compelling because of the ability to generate an “off-the-shelf” reagent that can be applied across patients. Whether such allogeneic tumor cells lines provide a more effective or less effective immunogen remains to be determined.


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