RT plus immunotherapy holds potential for sarcoma treatment
Advances in radiotherapy (RT) and immuno-oncology are poised to benefit sarcoma patients, many of whom do not respond to chemotherapy.
“While neoadjuvant and adjuvant RT is used for local control of soft tissue sarcoma [STS], it does not improve overall survival due to its inability to reach micrometastases,” said Professor Angela Hong of the University of Sydney in Sydney, Australia.
The immune system is found to play a role in RT response. In a study using a B16-SIY melanoma mouse model, nude mice’s tumours did not respond to RT, while wild-type mice with depleted CD8+ T lymphocyte levels showed some tumour response, but not of the same extent as wild-type controls. [Blood 2009;16:589-595].
“RT achieves an in situ vaccination effect by releasing tumour antigens, danger-associated molecular proteins, proinflammatory cytokines [IL-1β, TGF, FGF, TNF] and chemokines,” explained Hong. In addition, changes in endothelium enhance immune cell extravasation, causing local infiltration of dendritic cells, macrophages, antigen-specific T cells, as well as myeloid derived suppressor cells. Phenotypic analyses of antigen-specific CD8+ T cells reveal that RT increases the percentage of antigen-experienced effector memory T cells. [Lancet Oncol 2015;16:498-509; Cancer Immunol Res 2015;3:345-355]
Preclinical studies combining RT and immunotherapy have shown intriguing results, including effects outside of the radiation field – a phenomenon termed abscopal effect. Originally, immune-mediated abscopal effects were documented in contralateral shielded tumours after administering RT with Flt3-L. [Cancer Res 1999;59:6028-6032; Int J Radiat Oncol Biol Phys 2004;58:862-870] Subsequently, combining RT with anti–CTLA-4 antibody in breast and colorectal carcinoma mouse models produced abscopal effects that correlated with the frequency of interferon (IFN)γ+ CD8 T cells. [Clin Cancer Res 2009;15:5379-5388]
Moreover, melanoma and non-small-cell lung cancer (NSCLC) case reports provided evidence of synergy between RT and immune checkpoint blockade. [N Engl J Med 2012;366:925-931; Cancer Immunol Res 2013;1:365-372]
“Clinical data on the use of immunotherapy in STS, especially when combined with RT, is lagging behind melanoma and lung cancer, as it is a much rarer cancer. Therefore, international collaboration is necessary to recruit a sufficient number of patient to translate into an impactful clinical trial,” remarked Hong.
To date, two phase II trials have shown promising results of immunotherapy in STS. Nivolumab plus ipilimumab attained a 16 percent objective response rate (ORR) with a manageable safety profile, comparable to currently available treatment options, in the Alliance A097401 study, while pembrolizumab achieved an ORR of 18 percent and a 12-week progression-free survival rate of 55 percent in the SARC028 trial. [Lancet Oncol 2018;19:416-426; Burgess MA, et al, ASCO 2017, abstract 11008] SARC032 is an ongoing phase II trial of neoadjuvant pembrolizumab with RT and adjuvant pembrolizumab for high-risk STS. [Mowery YM, et al, ASCO 2018, abstract TPS11588]
Recent genomic studies have established different mutational burdens across sarcoma histologies. Genetically complex STS subtypes, such as undifferentiated pleomorphic sarcoma (UPS) and leiomyosarcoma (LMS), have high expression levels of genes related to antigen presentation and T‐cell infiltration, and may therefore be more likely to respond to immunotherapies. [Cancer 2017;123:3291-3304] Interestingly, the highest ORR (40 percent) attained in the SARC028 trial was within the UPS cohort treated with pembrolizumab, but no responses were observed among LMS patients. [Burgess MA, et al, ASCO 2017, abstract 11008]
“For most high-grade STS cases, traditional chemotherapy is of limited benefit, especially in the metastatic setting. The combination of immunotherapy with RT, which synergistically stimulate a systemic antitumour immune response, has the potential to improve survival through eliminating micrometastases,” concluded Hong.