Bioimmunoadjuvants for the treatment of neoplastic and infectious disease: Coley's legacy revisited

Abstract

In the nineteenth century, William B. Coley induced durable remission of inoperable metastatic sarcoma by repeatedly injecting live streptococcus bacilli and, subsequently, heat-killed bacterial extracts into the primary tumor. While Coley's contemporaries debated the veracity of his results, this bold treatment protocol established the new scientific field of immunology. In Coley's era, the scientific and medical communities lacked the prerequisite knowledge to validate and understand his treatment protocols. Today, a more comprehensive understanding of the human immune system, anchored by the discovery of the mammalian Toll-like receptor gene family in the 1990s, permits a mechanistic understanding of his results. Coley's cocktail of TLR agonists likely stimulated a complex cascade of cytokines, each of which plays a unique and vital role in the orchestration of the immune response. Here we explore Coley's legacy: a dissection of those cytokines which possess the immunostimulatory properties necessary to modulate the immune system and ameliorate human disease. The discussion is limited to molecules that have been able to show therapeutic promise in the clinical setting.

Introduction

In 1891, an inspired young surgeon named William B. Coley (Fig. 1) embarked upon an intellectual odyssey that would ultimately earn him the title “Father of Immunotherapy”; however, Coley's journey was not to be one of triumph and exultation, but rather a case study of resolve and determination in the face of implacable odds. Coley is a somewhat tragic figure whose contributions to immunology have mainly been recognized and appreciated posthumously. Haunted by the death of his first patient from metastatic sarcoma, Coley delved deeply into the historical record in search of a potential cure for cancer. What he found would entwine the seemingly unrelated conditions of cancer and infection as well as give birth to the nascent fields of immunology and immunotherapy, a remarkable achievement considering that immune cell mediators and their mechanisms of action (i.e. macrophage phagocytosis pictured in Fig. 2) were wholly unknown in his era. Coley found 47 case reports in which concomitant infection seemed to have caused the remission of an otherwise incurable neoplastic malignancy. His research even relied upon anecdotes from the pre-antiseptic era: eighteenth century surgeons reported oncologic cure rates of greater than 80% following resection or amputation, provided that the patient did not die from the inevitable infection that accompanied eighteenth century surgical procedures. Most striking to Coley was the apparent connection between erysipelas, a streptococcal skin infection, and the remission of soft tissue sarcoma.

When Coley began injecting his cancer patients with Streptococcus pyogenes (the causative agent of erysipelas) in 1891, he encountered some surprising impediments. Unexpectedly, it was very difficult to induce erysipelas in most patients and, once infection was established, it was difficult to cure patients of their invasive streptococcal disease. Two patients even died from disseminated septicemia. By 1893, Coley had settled upon an admixture of heat-killed S. pyogenes and heat-killed Bacillus prodigious (now reclassified as Serratia marcecsens). This fortuitous combination of Gram-positive and Gram-negative bacteria possessed a wide array of immunostimulatory properties that allowed Dr. Coley to achieve long-term cure rates unrivaled by medical science in the 73 years since his death (Table 1). Yet Coley's treatment protocol was doomed in his own lifetime by the contemporary development of radiotherapy and the absence of a definable, mechanistic explanation for infection-mediated tumor regression [1], [2], [3], [4], [5]. It is the century-long search for mechanism that today defines Coley's legacy. His initial observations have, in large part, led to the discovery of the soluble signaling factors that modulate immune function, as well as the pattern recognition receptors responsible for the detection of infectious organisms [6], [7], [8], [9]. Coley's legacy is perpetuated as we empirically adapt these physiologic immune modulators and TLR agonists for the optimal treatment of human disease.

While a large number of potential biological adjuvants have demonstrated anti-tumor efficacy in experimental systems, a relatively small number of these have been successfully translated to the clinic, and a correspondingly smaller number have demonstrated meaningful efficacy in human beings. Here we attempt to limit the scope of our review to those compounds that have either demonstrated significant efficacy in the clinic or seem likely to exhibit such in the near future (Table 2). Some powerful immune mediators such as IL-12 and IFN-γ are not discussed since they have shown little promise as stand alone immune therapies. Their efficacy seems to be limited to an adjuvant role in conjunction with vaccination, a topic which may be reserved for an independent discussion.