Clinical Evidence of Immunogenicity: Limb-Spare Infections in Osteosarcoma
The capacity for the immune system to recognize and eliminate cancer has been recognized for over a century with some of the earliest reports including the eradication of bone sarcomas. In the early 1890's, William Coley reported that accidental acquisition or intentional inoculation of the bacterium responsible for erysipelas (Streptococcus pyogenes) could result in regression or delayed recurrence of various cancers.[29, 30] These clinical insights eventually led to Coley's development of a vaccine consisting of 2 killed bacteria, Streptococcus pyogenes and Serratia marcescens. The vaccine was named “Coley's Toxins” and was efficacious in the treatment of a variety of tumor types, including bone sarcomas.
Coley's observations that underscored the potency of the immune system against cancer have been long recognized, but not until recently was direct in vivo evidence regarding infection-enhanced antitumor immunity for OS revisited and reported to the medical community. Although histologic evidence of non-eptic, chronic inflammation in biopsy specimens of canine OS has not been found to be prognostic, spontaneous regression of OS in dogs has been reported and dogs that experience acute bacterial infection secondary to limb-salvage surgery have been found to have increased survival times in several independent studies.[34-37] The initial observation of this finding was reported in a study investigating the use of radiation therapy before cortical allograft limb-sparing surgery in dogs with high-grade appendicular OS. Although radiotherapy before limb-sparing surgery was deemed detrimental for achieving durable fixation of bone allografts, a significant increase in survival time was noted between dogs whose allograft became infected as compared to dogs with allografts that remained uninfected (11 versus 5 mos respectively).
These initial findings later were corroborated by 2 additional studies that examined the outcome of dogs with OS treated with limb-sparing surgery and adjuvant chemotherapy.[35, 36] Dogs with distal radial OS that developed cortical allograft infection were half as likely to die and half as likely to develop metastatic disease as compared to dogs without infection, which resulted in a significant difference in median survival time (MST) of 18 versus 7.6 mos respectively. Similar findings were reported in dogs undergoing either cortical allograft or endoprosthetic limb-sparing surgery. No difference in MST was found between the 2 surgical groups but MST was found to be significantly longer in dogs that experienced construct failure (22.8 versus 10.7 mos) or postoperative infection (22.8 versus 9.6 mos). Dogs with postoperative infection also were 25 times less likely to die, and median metastasis-free interval (MFI) was increased for dogs with infection (18.5 versus 9.1 mos). All dogs with construct failure also had postoperative infections, and irritation secondary to construct failure might have contributed to infection development. Lastly, in a recent retrospective study, when evaluating only dogs that lived for >1 year after histopathologic diagnosis of OS, increased survival time of dogs that developed postoperative limb-spare infections also was identified. Dogs with limb-spare infections had a MST of 6 mos beyond 1 year, whereas dogs that underwent limb-sparing surgery but did not acquire infection only achieved a MST of 0.9 mos beyond 1 year.
People with OS who were treated by endoprosthetic replacement and experienced postoperative infection also had increased survival time. A later study, however, found no difference in survival time between infected and noninfected patients when matched for type of chemotherapy, histologic response, tumor size and location, and local recurrence. No case–control studies for comparison have been performed in dogs to date, but the majority of studies do suggest that nonspecific immune stimulation secondary to infection prevents the recurrence or delays progression of OS in a clinical setting.
The immune mechanisms that contribute to increased survival secondary to limb-spare infection have not been well-studied, but evidence for innate system involvement on the suppression of OS growth has been derived from a murine model of chronic bacterial osteomyelitis. In this study, osteomyelitis decreased tumor growth and increased survival time in mice when tumors were established after infection, but this effect was abrogated when tumors were established before induction of osteomyelitis. Several different types of infectious agents have been cultured in affected dogs,[34-36] and infection-associated inhibition of tumor growth in the murine model of chronic bacterial osteomyelitis was not dependent on the specific infectious agent involved. Increased circulating and splenic inflammatory monocytes as well as increased tumor-associated macrophages (TAM) were observed in infected mice, and depletion of natural killer (NK) cells or monocytes and macrophages was found to reverse the tumor growth inhibition seen with concurrent osteomyelitis. These observations led the authors to conclude that both NK cells and monocytes and macrophages are associated with the innate antitumor response elicited by chronic bacterial osteomyelitis, and they speculated that the increase in inflammatory monocytes was associated with repopulation of activated TAM, which were expected to be tumor-inhibitory in this setting rather than tumor-promoting. Furthermore, the finding of increased NK cells might be related to back-and-forth activation between NK cells and monocytes, also contributing to tumor inhibition.
These clinical and preclinical studies strongly suggest that OS is an immunogenic neoplasm, and micrometastatic disease potentially can be controlled or eliminated after recognition by the immune system. Case–control studies in dogs to either confirm or refute these findings and mechanistic studies to characterize the specific immune responses against OS cells elicited by limb-spare infections are lacking.