NON-CHEMOTHERAPEUTIC APPROACHES IN REFRACTORY PEDIATRIC SARCOMA INCLUDING NEWER ADVANCES

Metronomic Therapy

Metronomic therapy is low-dose, prolonged, continuous administration of drugs that inhibits angiogenesis.154,155 Metronomic therapy was shown to be safe and well tolerated in a study of 16 children with relapsed/refractory patients which included five patients with OGS.156 A randomized controlled trial comparing metronomic therapy with placebo, in extracranial non-hematopoietic paediatric solid tumours, post lines of chemotherapy were done to evaluate the role of metronomic therapy with the proportion of patients without disease progression as an endpoint. There was no significant difference between the two groups. However, in post hoc subgroup analysis patients who received more than three cycles and did not have bone sarcoma benefited with metronomic therapy.157 Metronomic therapy needs to be explored in a palliative setting, in clinical trials designed for this group of patients.


Continue Reading

Immune Check-Point Inhibitors

Few STS[1–5%] may have genomic instability in the form of Microsatellite instability [MSI], such as MSI-H, which is the biologic basis of deficient mismatch repair (dMMR).158 They may respond to anti-programmed death receptor 1 [PDl] or anti-programmed death receptor ligand 1 [PDL1] inhibitors. Recently FDA has approved pembrolizumab, a PD1 inhibitor as a treatment option in certain advanced solid tumours including STS that are refractory to standard of care therapy which are MSI-H or dMMR.159 PD-1–expressing TILs and tumour PD-L1 expression were seen in 65% and 58% of tumours in 105 cases of various STS sub-types. Initial immunotherapy trials did show a modest response in advanced STS with few tumour types showed predominantly stable disease.160–163 Second study showed encouraging results in some adult-type STS [dedifferentiated liposarcoma & undifferentiated pleomorphic sarcoma] but none in paediatric sarcoma.111

Ipilimumab a CTLA4 immune checkpoint inhibitor was evaluated in Phase I clinical trial for refractory pediatric sarcoma which included OGS and RMS. No objective responses were seen.161 Similarly, a phase I/II trial in relapsed refractory Ewing’s sarcoma and OGS using nivolumab and combination of nivolumab plus ipilimumab did not show any objective response.163

Immunotherapy probably will not be as effective as in adult oncology because pediatric cancers have less tumor mutational burden, immune system in children is still maturing and regulatory T cells present in the microenvironment of pediatric sarcomas have high immunosuppressive action which hinders immunotherapy.72 Many clinical trials ongoing on refractory STS evaluating the role of immunotherapy and the majority of them include adult patients with STS (Table 5).

Cancer Vaccines

Dendritic cell vaccine is a novel approach that appears to be promising. In metastatic and refractory pediatric sarcoma autologous lymphocyte infusion plus sequential autologous tumor lysate vaccines were administered as adjuvant therapy after completion of conventional therapy. Five-year survival was 63% in patients with EWS and RMS and 74% in patients who did not have any residual disease after conventional therapy.164

CAR-T Therapy

In view of the limitations of immune checkpoint inhibitors in refractory pediatric sarcoma, CAR-T cells have generated a lot of interest. The key challenges lie in the rarity of the disease and finding an appropriate target. To circumvent these problems current research is focussing on developing CAR-T cells against antigens which are present in other tumors as well as refractory pediatric tumors.165 Phase I clinical trials of EGFR as CAR-T cells as target in OS, RMS and EWS (NCT03618381) are going on. GD2 is another target of CAR-T cells that are currently being tried in OGS, EWS and sarcoma (NCT01953900, NCT02107963, NCT03356782). Infantile fibrosarcoma with a high level of tumor-infiltrating lymphocytes with high expression of costimulatory molecules suggests that adoptive T-cell therapy could be an option.166

Promising Immunotherapeutic Approaches in Pediatric Sarcomas

Paediatric sarcomas express fewer neoantigen than adult type and distinguish them distinctly from adult STS in terms of pathogenesis as well as response to immune checkpoint inhibitors.167 Neoantigen expression is vital for immune cell infiltration in the tumor microenvironment and subsequent immune-mediated cell killing. The discovery of neoantigen and development of directed therapy is of paramount importance. Surface targets such as ganglioside GD2 and GD3 are expressed in paediatric sarcomas and also IGF1R in Ewing’s sarcoma. These surface antigens can be targeted with advanced targeted therapy including CAR-T cell therapy.168

However, it is pertinent to note that novel therapeutical approaches that have been successful in other cancers have not yet impacted the management of pediatric sarcoma patients. INFORM study and other studies using the “omics” approach have generated huge genetic, epigenetic, gene expression data along with the identification of new driver mutations, but patients have not benefited in terms of survival from this genetic data acquisition. Immunotherapy with conventional targets has failed in pediatric refractory sarcomas. Drug screens have identified new drugs and are currently under trials, but proof of efficacy is lacking.

FUTURE DIRECTION

Systemic combination chemotherapy has reached a plateau in terms of cure rate & survival after huge success over the last 3 decades and has complemented by advanced surgical techniques, improved quality of life with limb salvage therapy and better prosthesis with newer engineering and improved radiation technique sparing short- & long-term treatment-related toxicities. Now, the focus is on further improving the survival, lowering long-term treatment-related toxicities, better salvage therapy in case of recurrent disease and to find the cure with research & development of newer therapeutics for metastatic disease. Newer targets in refractory sarcomas are shown in Figure 1.

Figure 1

Various immunotherapeutic approaches – both as single agents and in combination are in clinical studies or published with the mixed outcome and some are promising.169 Chemo-immunotherapy combination therapies can be one of the potential strategies in those with a high burden or upfront metastatic disease after the huge success of the same approach in non-small cell lung cancer.170 Cellular vaccine171 & adaptive cell therapy,172 defining kinome and development of small molecule targeted therapies [NCT02601950] are emerging & theoretically promising treatment strategies in paediatric sarcoma especially translocation associated sarcomas.

Maintenance immunotherapeutic strategy after completion of definitive initial treatment may improve the long-term outcome just like PACIFIC173 study demonstrated huge success of Durvalumab [an anti-PDL1 antibody] in stage 3 NSCLC after definitive chemoradiation and should be investigated in paediatric sarcomas. A strategy that decreases the chance of recurrence in paediatric sarcomas should be a better strategy rather than treating them on recurrence.

In the case of treatment refractoriness, a newer immunotherapeutic strategy like CAR-T cells can be an emerging & promising therapy that can cure even treatment-resistant cases, just like in haematological malignancies. International and national collaboration of multi-pronged treatment strategy, personalized & precision medicine and a better understanding of tumour genome, identification of treatment resistance mechanism, exploitation of host immunity remains the future treatment strategy in the management of relapsed & refractory paediatric sarcomas.

READ FULL ARTICLE Curated publisher From Dovepress