Abstract
Cancer cells can escape the immune system by different mechanisms. The evasion of cancer cells from immune surveillance is prevented by immune checkpoint inhibitors, allowing the patient’s own immune system to attack their cancer. Immune checkpoint inhibitors have shown improvement in overall survival for melanoma, lung cancer and renal cell carcinoma in clinical trials. Unfortunately, not all patients respond to this therapy.
In cancer management, percutaneous ablation techniques are well established for both cure and local control of many tumour types. Cryoablation of the tumour tissue results in cell destruction by freezing. Contrary to heat-based ablative modalities, cryoablation induces tumour cell death by osmosis and necrosis. It is hypothesised that with necrosis, the intracellular contents of the cancer cells stay intact allowing the immune system to induce an immune-specific reaction. This immune-specific reaction can, in theory, also affect cancer cells outside the ablated tissue, known as the abscopal effect. Unfortunately, this effect is rarely observed, but when cryoablation is combined with immunotherapy, the effect of both therapies may be enhanced. Although several preclinical studies demonstrated a synergistic effect between cryoablation and immunotherapy, prospective clinical trials are needed to prove this clinical benefit for patients. In this review, we will outline the current evidence for the combination of cryoablation with immunotherapy to treat cancer.
Keywords: Cryoablation, Immunotherapy, Cancer, Immune checkpoint inhibitor
https://www.ncbi.nlm.nih.gov/pmc/articl ... n_sectitle
Cryoablation and immunotherapy: an overview of evidence on its synergy
Re: Cryoablation and immunotherapy: an overview of evidence on its synergy
“Key points
It is hypothesised that cell death by cryoablation leaves the intracellular contents of the cancer cells intact for the immune system to induce an immune-specific reaction also known as the abscopal effect.
Immunotherapy uses the immune system for treatment of the tumour, but not all patients respond to immunotherapy.
Combination of cryoablation with immunotherapy may enhance the effect of both therapies for better tumour destruction.”
It is hypothesised that cell death by cryoablation leaves the intracellular contents of the cancer cells intact for the immune system to induce an immune-specific reaction also known as the abscopal effect.
Immunotherapy uses the immune system for treatment of the tumour, but not all patients respond to immunotherapy.
Combination of cryoablation with immunotherapy may enhance the effect of both therapies for better tumour destruction.”
Debbie
Re: Cryoablation and immunotherapy: an overview of evidence on its synergy
“Results
Cryoablation and the immune system
Cryoablation may be synergistic with the immune system in the way cell death is induced. After ablation, the tumour remains, releasing various factors attracting the immune system. A proposed theory regarding the potential mechanisms of cryoablation and the immune system is the danger theory of Matzinger [14, 15]. This theory proposes that after cell death by necrosis, cells secrete danger signals. These danger signals can initiate an immune response. In addition, these signals can mature dendritic cells (DCs) to fully activate T cells which may lead to a specific immune response. Cryoablation induces cell death by necrosis in which intracellular contents are still preserved while DNA, RNA and heat shock protein (HSP), which can induce danger signals, are released [16]. On the other hand, the cells in the outer margin of cryoablated tissue die from apoptosis and do not release DNA, RNA and HSP, and with no danger signal, the DCs remain immature. Immature DCs may trigger immune suppressive signals that could lead to anergy (T cell inactivation) [17, 18]. Therefore, cryoablation can induce both an immunostimulatory and immunosuppressive response (Fig. 2).”
Cryoablation and the immune system
Cryoablation may be synergistic with the immune system in the way cell death is induced. After ablation, the tumour remains, releasing various factors attracting the immune system. A proposed theory regarding the potential mechanisms of cryoablation and the immune system is the danger theory of Matzinger [14, 15]. This theory proposes that after cell death by necrosis, cells secrete danger signals. These danger signals can initiate an immune response. In addition, these signals can mature dendritic cells (DCs) to fully activate T cells which may lead to a specific immune response. Cryoablation induces cell death by necrosis in which intracellular contents are still preserved while DNA, RNA and heat shock protein (HSP), which can induce danger signals, are released [16]. On the other hand, the cells in the outer margin of cryoablated tissue die from apoptosis and do not release DNA, RNA and HSP, and with no danger signal, the DCs remain immature. Immature DCs may trigger immune suppressive signals that could lead to anergy (T cell inactivation) [17, 18]. Therefore, cryoablation can induce both an immunostimulatory and immunosuppressive response (Fig. 2).”
Debbie
Re: Cryoablation and immunotherapy: an overview of evidence on its synergy
Results continued..
“In addition, cytokines are produced after cryoablation, and these can also influence an immune response. Again, both immunosuppressive and immunostimulatory cytokines may be released depending on the tumour tissue, age and freeze rate [19]. For cryoablation of liver tumours, when more than 20% of the liver volume is ablated, a systemic inflammatory response can occur due to a release of cytokines interleukine-6 (IL-6), IL-10 and tumour necrosis factor alpha (TNFα), which can have marked systemic effects [7, 20–22]. Therefore, cryoablation is not the preferred treatment since heat-based ablations are better established in this setting [23]. In addition, cytokines are produced after cryoablation, and these can also influence an immune response. Again, both immunosuppressive and immunostimulatory cytokines may be released depending on the tumour tissue, age and freeze rate [19]. For cryoablation of liver tumours, when more than 20% of the liver volume is ablated, a systemic inflammatory response can occur due to a release of cytokines interleukine-6 (IL-6), IL-10 and tumour necrosis factor alpha (TNFα), which can have marked systemic effects [7, 20–22]. Therefore, cryoablation is not the preferred treatment since heat-based ablations are better established in this setting [23]. Yet, two clinical studies reported favourable outcomes on overall survival when cryoablation was combined with immunotherapy of allogenic natural killer (NK) cell infusion and dendritic cell cytokine-induced killer (DC-CIK) cells [24, 25].
Cryoablation combined with allogenic natural killer cell immunotherapy improves the curative effect in patients with advanced hepatocellular cancer
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669863/
Abstract
In this study, the clinical efficacy of cryosurgery combined with allogenic natural killer cell immunotherapy for advanced hepatocellular cancer was evaluated. From October 2015 to March 2017, we enrolled 61 patients who met the enrollment criteria and divided them into two groups: 1) the simple cryoablation group (Cryo group, n = 26); and 2) the cryoablation combined with allogenic natural killer cells group (Cryo-NK group, n = 35), the safety and short-term effects were evaluated firstly, then the median progression-free survival, response rate and disease control rate were assessed. All adverse events experienced by the patients were recorded, and included local (e.g., pain, pleural effusion, and ascites) and systemic (e.g., chills, fatigue, and fever) reactions, fever was more frequent. Other possible seriously side effects (e.g., blood or bone marrow changes) were not detected. Combining allogeneic natural killer cells with cryoablation had a synergistic effect, not only enhancing the immune function, improving the quality of life of the patients, but also reducing the expression of AFP and significantly exhibiting good clinical efficacy of the patients. After a median follow-up of 8.7 months (3.9 –15.1months), median progression-free survival was higher in Cryo-NK (9.1 months) than in Cryo (7.6 months, P = 0.0107), median progression-free survival who received multiple natural killer was higher than who just received single natural killer (9.7 months vs.8.4 months, P = 0.0011, respectively), the response rate in Cryo-NK (60.0%) was higher than in Cryo (46.1%, P < 0.05), the disease control rate in Cryo-NK (85.7%) was higher than in Cryo group (69.2%, P < 0.01). Percutaneous cryoablation combined with allogeneic natural killer cell immunotherapy significantly increased median progression-free survival of advanced hepatocellular cancer patients. Multiple allogeneic natural killer cells infusion was associated with better prognosis to advanced hepatocellular cancer.
Keywords: curative effect, percutaneous cryoablation, allogenic natural killer cell, hepatocellular cancer, progression-free survival
“In addition, cytokines are produced after cryoablation, and these can also influence an immune response. Again, both immunosuppressive and immunostimulatory cytokines may be released depending on the tumour tissue, age and freeze rate [19]. For cryoablation of liver tumours, when more than 20% of the liver volume is ablated, a systemic inflammatory response can occur due to a release of cytokines interleukine-6 (IL-6), IL-10 and tumour necrosis factor alpha (TNFα), which can have marked systemic effects [7, 20–22]. Therefore, cryoablation is not the preferred treatment since heat-based ablations are better established in this setting [23]. In addition, cytokines are produced after cryoablation, and these can also influence an immune response. Again, both immunosuppressive and immunostimulatory cytokines may be released depending on the tumour tissue, age and freeze rate [19]. For cryoablation of liver tumours, when more than 20% of the liver volume is ablated, a systemic inflammatory response can occur due to a release of cytokines interleukine-6 (IL-6), IL-10 and tumour necrosis factor alpha (TNFα), which can have marked systemic effects [7, 20–22]. Therefore, cryoablation is not the preferred treatment since heat-based ablations are better established in this setting [23]. Yet, two clinical studies reported favourable outcomes on overall survival when cryoablation was combined with immunotherapy of allogenic natural killer (NK) cell infusion and dendritic cell cytokine-induced killer (DC-CIK) cells [24, 25].
Cryoablation combined with allogenic natural killer cell immunotherapy improves the curative effect in patients with advanced hepatocellular cancer
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669863/
Abstract
In this study, the clinical efficacy of cryosurgery combined with allogenic natural killer cell immunotherapy for advanced hepatocellular cancer was evaluated. From October 2015 to March 2017, we enrolled 61 patients who met the enrollment criteria and divided them into two groups: 1) the simple cryoablation group (Cryo group, n = 26); and 2) the cryoablation combined with allogenic natural killer cells group (Cryo-NK group, n = 35), the safety and short-term effects were evaluated firstly, then the median progression-free survival, response rate and disease control rate were assessed. All adverse events experienced by the patients were recorded, and included local (e.g., pain, pleural effusion, and ascites) and systemic (e.g., chills, fatigue, and fever) reactions, fever was more frequent. Other possible seriously side effects (e.g., blood or bone marrow changes) were not detected. Combining allogeneic natural killer cells with cryoablation had a synergistic effect, not only enhancing the immune function, improving the quality of life of the patients, but also reducing the expression of AFP and significantly exhibiting good clinical efficacy of the patients. After a median follow-up of 8.7 months (3.9 –15.1months), median progression-free survival was higher in Cryo-NK (9.1 months) than in Cryo (7.6 months, P = 0.0107), median progression-free survival who received multiple natural killer was higher than who just received single natural killer (9.7 months vs.8.4 months, P = 0.0011, respectively), the response rate in Cryo-NK (60.0%) was higher than in Cryo (46.1%, P < 0.05), the disease control rate in Cryo-NK (85.7%) was higher than in Cryo group (69.2%, P < 0.01). Percutaneous cryoablation combined with allogeneic natural killer cell immunotherapy significantly increased median progression-free survival of advanced hepatocellular cancer patients. Multiple allogeneic natural killer cells infusion was associated with better prognosis to advanced hepatocellular cancer.
Keywords: curative effect, percutaneous cryoablation, allogenic natural killer cell, hepatocellular cancer, progression-free survival
Debbie
Re: Cryoablation and immunotherapy: an overview of evidence on its synergy
Hello Olga
I'm trying to better understand the scheduling of ICIs and cyro surgeries.
Is the above article suggesting that the ICI was administered within four days after the cyro?
Thanks in advance. :)
I'm trying to better understand the scheduling of ICIs and cyro surgeries.
Is the above article suggesting that the ICI was administered within four days after the cyro?
Thanks in advance. :)
Debbie
Re: Cryoablation and immunotherapy: an overview of evidence on its synergy
The general understanding at this point seems to suggest that the ablations should be scheduled few days before/after the immunotherapy to work in synergy. Look on the clinical trials dot gov for any newer immunotherapy trials open in combination with ablative therapies - I usually check the trial suggested regimens for what is assumed as the most promising one. Look for any - SBRT, radiation therapy, cryoablation, RFA - just to see how they schedule it
Olga