Abstract
Since the 1920s the gold standard for treating cancer has been surgery, which is typically preceded or followed with chemotherapy and/or radiation, a process that perhaps contributes to the destruction of a patient’s immune defense system. Cryosurgery ablation of a solid tumor is mechanistically similar to a vaccination where hundreds of unique antigens from a heterogeneous population of tumor cells derived from the invading cancer are released. However, releasing tumor-derived self-antigens into circulation may not be sufficient enough to overcome the checkpoint escape mechanisms some cancers have evolved to avoid immune responses. The potentiated immune response caused by blocking tumor checkpoints designed to prevent programmed cell death may be the optimal treatment method for the immune system to recognize these new circulating cryoablated self-antigens. Preclinical and clinical evidence exists for the complementary roles for Cytotoxic T-lymphocyte-associated protein (CTLA-4) and PD-1 antagonists in regulating adaptive immunity, demonstrating that combination immunotherapy followed by cryosurgery provides a more targeted immune response to distant lesions, a phenomenon known as the abscopal effect. We propose that when the host’s immune system has been “primed” with combined anti-CTLA-4 and anti-PD-1 adjuvants prior to cryosurgery, the preserved cryoablated tumor antigens will be presented and processed by the host’s immune system resulting in a robust cytotoxic CD8+ T-cell response. Based on recent investigations and well-described biochemical mechanisms presented herein, a polyvalent autoinoculation of many tumor-specific antigens, derived from a heterogeneous population of tumor cancer cells, would present to an unhindered yet pre-sensitized immune system yielding a superior advantage in locating, recognizing, and destroying tumor cells throughout the body.
Highlights
In the era of molecular medicine, the oncology field still faces many extreme challenges extending survival rates to all stage III and IV cancers with many cancers remaining arduous to treat
Altering the host’s immune system by blocking these checkpoints designed to prevent programmed cell death may be instrumental in allowing the immune system to recognize these new cryoablated circulating self-antigens, thereby potentially causing a robust immune response to kill distant metastases; a phenomenon known as the abscopal effect
There exists numerous reports in the literature where the abscopal effect has been observed when patients who were previously treated with CTLA-4 and PD-1 antibodies subsequently received radiation therapy, and their distant metastases regressed (Table 2) [38]. This abscopal effect is believed to be mediated by the development of a systemic antitumor immune response caused by radiation therapy, which releases intratumoral antigens adjacent to Antigen-presenting cells (APCs) and T-cells; quite similar if not identical to the immune response resultant of cryoablation
Summary
In the era of molecular medicine, the oncology field still faces many extreme challenges extending survival rates to all stage III and IV cancers with many cancers remaining arduous to treat. Exogenous antigens are typically expressed on cells that exhibit MHC class II molecules whereas intracellular or endogenous antigens are expressed by cells with MHC class I molecules [21] How these antigens are presented and processed, and the subsequent balance and homeostasis set-point of the MHC Class cellular response and their cytokine profile that develops will dictate the T-cell and cytotoxic response which results in destruction and killing of the invading organism or cancer cell senescence [22]. The ratio of Tregs to T-effector cells and their subsequent cytokine profile dictate and control this “set-point,” representing the most efficient and safest mechanism to eradicate the invading organism while protecting the host This balance is necessary, as an exaggerated response can occur which may result in autoimmune disease or processes such as persistent inflammatory compensatory syndrome; resulting in damage to the patient’s physiology. A highly active T-cell co-stimulatory signal is controlled by CD28 which binds to B7-1 (CD80) and B7-2 (CD86) ligands on APCs and induces T-cell proliferation
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call