Keywords
immune microenvironment - ablation - interventional oncology - immunotherapy
Interventional oncology (IO) has seen remarkable progress over the last two decades
to now offer a variety of locoregional cancer treatments. The minimally invasive nature
of IO was the main driver for the specialty's emergence and growth, particularly as
an alternative to traditional surgical and systemic treatments. With the degree of
image resolution offered by current clinical imaging technologies, the efficacy of
IO therapies is now well established at the tissue or organ level.
Recent advancements in immunooncology research have brought a new “magnifying glass”
to IO, namely, one focusing on the immune microenvironment. The effect of IO therapeutics
is now investigated at the cellular and molecular level with a focus on the immune
system. A unique feature of IO therapy is particularly pertinent in these investigations:
IO achieves in situ destruction, during which tumor-specific neoantigens are released
and potentially inducing the so-called abscopal effect or in vivo antitumor vaccination.[1]
[2] In addition, the spontaneous remission of distant malignant disease after focal
thermal ablation has been reported occasionally, but the exact mechanism remains elusive.[3]
[4]
[5]
[6]
Current tumor ablation techniques rely on extreme temperatures to induce irreversible
cellular injury and result in tissue coagulative necrosis. The commonly used techniques
include radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation,
while the newer techniques such as laser and high intensity focused ultrasound (HIFU)
have demonstrated promising results. While not based on thermal energy, irreversible
electroporation (IRE) is also employed along with the aforementioned thermal ablation
methods.
The aim of this article is to provide a review on the immune microenvironment in relation
to current image-guided ablation techniques and to discuss current and upcoming developments
of novel IO strategies to take advantage of antitumor immunity.
Cancer-Immunity Cycle
Antitumor immunity involves a series of events referred to as the cancer-immunity
cycle[7] ([Fig. 1]). Oncogenic neoantigens expressed by tumor cells are processed by antigen-presenting
cells (APCs) to prime and activate antigen-specific CD8+ cytotoxic T-lymphocytes (CTLs)
at tumor-draining lymph nodes (TDLNs). These activated effector cells travel via systemic
circulation and carry out their tumor-killing function when they encounter their specific
antigen expressed within the tumor beds.
Fig. 1 Postablation immune microenvironment: cancer-immunity cycle. The area of thermal
ablation can be divided into three different zones: central necrotic, peripheral transitional,
and normal surrounding tissues. Cancer neoantigens released from cellular injury or
death will activate the cancer-immunity cycle, generating tumor-specific immune effectors.
These activated effector cells travel via systemic circulation and carry out their
tumor-killing function when they encounter their specific antigen expressed within
the tumor beds. However, there are multiple negative regulatory mechanisms at each
step of the cancer-immunity cycle, preventing meaningful and therapeutic anticancer
effect provided solely by the immune system. Multiple immunomodulatory strategies
have been combined with image-guided locoregional ablation to synergistically shift
the equilibrium out of inhibitory immune modulation (red boxes).
Despite successful initial priming of CTLs,[8]
[9] subsequent clonal expansion leading to an effector population rarely comes to completion.[7] There are multiple negative regulatory mechanisms at each step of the cancer immunity
cycle, preventing meaningful and therapeutic anticancer effects provided solely by
the immune system. This can explain anecdotal reports of effective immunotherapy throughout
the history of immuno-oncology including original observations by Fehleisen, Busch,
and Coley.[3]
[4]
[5]
[6]
[10]
[11]
[12] Additionally, the tumor cell population can escape the immune system's immunoediting,
where tumor cells evade immune surveillance, by promoting the selective survival of
the immune-resistant antigen cohort.[13]
[14]
[22] The goal of cancer immunotherapy is to modulate negative regulatory mechanisms and
induce an effective cancer elimination process without creating an overt autoimmune
reaction or accelerating the immunoediting process. Recent successes in systemic immune
checkpoint inhibitors such as anti-PD1 (programmed cell death protein 1), anti-PDL1
(programmed death ligand 1), and anti-CTLA4 (cytotoxic T-lymphocyte associated protein
4) therapies are examples of these efforts.
Cellular Injury and Immunogenicity of Thermal Ablative Therapy
Cellular Injury and Immunogenicity of Thermal Ablative Therapy
Currently available ablative therapies, with the exception of IRE, rely on heat-based
cellular destruction methods. RFA, MWA, HIFU, and laser ablation induce hyperthermic
cellular damage, while cryoablation induces cellular injury by freezing. Regardless
of the technique, thermal ablation can be divided into three zones: central necrotic,
peripheral transitional, and normal tissue[15]
[16]
[17] ([Fig. 1]). The central area is characterized by direct and immediate cellular injury achieved
by lethal temperatures, that is, greater than 60°C in hyperthermic methods and below
−20°C in cryoablation.[15]
[16] The peripheral or transitional zone is a band-like area of thermal conduction between
the central necrotic zone and surrounding normal tissue, characterized by a steep
temperature gradient toward normal tissue temperature. Within the peripheral zone,
different degrees of cellular injury will result in a mixture of necrotic, delayed/indirect,
and reversible injury. This is also the area where most of the immune and inflammatory
cellular infiltrates are found.[15]
[18] Delayed or indirect cellular injury can manifest via many different mechanisms including
apoptosis, ischemia–reperfusion, and innate and adaptive immune response.[16]
Cellular necrosis immediately releases immunogenic intracellular contents (such as
DNA, RNA, and heat shock proteins [HSPs]) directly into the extracellular matrix.
Unlike necrosis, apoptosis is a much more intrinsic process of cell death and is less
immunogenic or inflammatory.[19] The ratio between postablation apoptosis and necrosis may be a key modulator to
achieving a maximally immunogenic microenvironment.[15] Some authors also suggest that different immunogenic qualities can be achieved by
modifying ablation protocols or parameters.[18]
[20]
Postablation Inflammation: Immunogenic versus Prooncogenic
Postablation Inflammation: Immunogenic versus Prooncogenic
All image-guided ablative therapies create in situ tissue damage which induces not
only an immunogenic response but also local wound healing and a systemic inflammatory
response. Postablation inflammation is well established clinically, with symptomatic
treatment generally being applied in a conservative manner. At the molecular level,
tissue remodeling upregulates and releases many prooncogenic growth factors and cytokines.[21] There is experimental and clinical evidence of worse outcomes of ablation therapy
with accelerated local or off-target tumor progression,[18]
[22]
[23]
[24]
[25]
[26]
[27] suggesting that a postablation microenvironment was potentially prooncogenic. In
animal HCC model, RFA was associated with increased tumor burden and decreased survival
compared with partial hepatectomy or sham controls.[27] Furthermore, this prooncogenic effect of RFA was attenuated by postablation systemic
inhibition of c-met signaling.[27] In another animal study with breast cancer, RFA of the normal liver was associated
with the growth of a distant tumor, which could also be suppressed by c-met inhibition.[22] In a separate study, the same group also reported a tumorigenic effect observed
with MWA which was attenuated by high-power, faster MWA protocol.[18]
Several efforts have been made to unfold the enigma of postablation inflammation by
characterizing peripheral blood mononuclear cell (PBMC) samples. In a study with 193
patients with CRLM (colorectal liver metastases) treated with RFA, elevated lymphocyte–monocyte
ratio (LMR) was identified as a significant negative predictor for recurrence and
mortality.[28] Decreased post-RFA neutrophil–lymphocyte ratio (NLR) was associated with improved
disease-free survival in 178 small hepatocellular carcinoma (HCC) patients,[29] while increased postablation NLR was associated with local recurrence and metastatic
disease in patients with 185 renal cell carcinoma (RCC) patients treated with RFA.[30] Additionally, an increase in the number of interferon gamma (IFN-γ) producing cytotoxic
natural killer (NK) cells was associated with longer disease-free survival after RFA
in 37 subjects with HCC.[31]
Methods of Ablation and Immune Stimulation
Methods of Ablation and Immune Stimulation
As RFA is the oldest technique, there are many studies in the literature regarding
the postablation immune reaction of this technique. Within hours or days after RFA,
there is a local and systemic release of proinflammatory cytokines, including IL (interleukin)-1β,
IL-1α, IL-6, IL-8, IL-18, and TNFα (tumor necrosis factor α).[21]
[32]
[33]
[34]
[35] Intriguingly, anti-inflammatory cytokines such as IL-10 and transforming growth
factor-beta are also shown to be released and upregulated after RFA.[35]
[36] Some studies have reported contradictory findings regarding the regulation of specific
cytokines, reflecting the complex and dynamic nature of the process.[33]
[36]
[37] Apart from cytokines, an important immune modulator found in the post-RFA microenvironment
is the extracellular heat shock protein (HSP).[38]
[39]
[40]
[41] HSP belongs to a group of endogenous molecules and is known as a “danger signal”
released by necrotic cells. Extracellular HSP70 is a chaperone molecule facilitating
the antigen presentation of APCs to T-cells[42]
[43] and is upregulated in the tumor microenvironment.[38]
[39]
[40]
[41] In a study with 22 posthepatic RFA subjects, serum HSP70 level was significantly
elevated within 24 hours and was positively associated with survival benefits and
time to disease progression.[44] Although it was first discovered in a post-RFA setting, HSP upregulation and release
have also been identified in other ablative modalities.[45]
[46]
[47]
[48] Additional danger signal molecules such as high-morbidity group box-1 (HMGB-1) are
under investigation regarding their role in postablation immune reaction.[49]
[50]
Cryoablation has been shown to induce a more robust systemic immune reaction compared
with hyperthermic ablative methods in multiple experimental and clinical studies.[21]
[32]
[51]
[52] Furthermore, postablation systemic or remote inflammatory organ injuries, the so-called
cryoshock, have been reported after large-volume cryoablation.[53]
[54]
[55]
[56] The hyper-immunogenicity of cryoablation is hypothesized to be due to the relative
preservation of tumor neoantigens during freezing cell injury compared with hyperthermal
ablation techniques. In cryoablation, osmotic changes across intra- and extracellular
compartments induce cellular injury without affecting the potential intracellular
tumor antigens including DNA, RNA, or proteins. Conversely, hyperthermal ablation
denatures and degrades proteins, erasing part of the critical tumor immunogenic footprints.
MWA appears to induce the least magnitude of immune or inflammatory reaction. In the
animal liver, a significantly lower level of inflammatory cytokines (IL-1β and IL-6)
and HSP70 in peripheral blood samples was observed after MWA compared with RFA or
cryoablation.[32]
[48] In another animal study, the level of proinflammatory cytokines after MWA was similar
to that of the surgical resection group that did not have any ablation.[23] Thus, eventually, the low inflammatory characteristic of MWA enables it to achieve
a successful larger volume hepatic ablation without collateral inflammatory remote
organ injuries.[48]
[57] Nevertheless, despite these reproducible observations, the exact mechanism for minimal
immune or inflammatory response after MWA remains unknown.
HIFU destroys cells mechanically by acoustic cavitation and histotripsy.[58]
[59]
[60] Acoustic cavitation results from the repeated growth and collapse of micro gas bubbles
within the tissue under the influence of high-pressure sound waves. Mechanical fractionation
combined with a boiling process enables histotripsy which eventually generates an
emulsified acellular homogenate surrounded by very thin, less than 1 mm, margins,
with minimal fibrosis.[58]
[59]
[60] This liquefied lesion is absorbed rapidly by the surrounding tissue and easily infiltrated
by immune cells. In a clinical study with 48 breast cancer subjects, HIFU-treated
lesions were removed by mastectomy and demonstrated markedly increased immune cell
infiltrates compared with surgical specimens not treated with HIFU.[61]
Laser ablation has had limited use in tumors and little data are available on its
immune stimulation. Similar to other hyperthermal techniques, a postablative increase
of proinflammatory cytokines in peripheral blood has been observed.[62] In preclinical animal experiments, tumor-specific immune cell generation has also
been observed after laser ablation.[63]
[64]
IRE is the newest ablation technique and does not incorporate thermal energy. IRE
selectively disrupts the lipid bilayer cellular membrane via the electrical induction
of permanent nanopores. Preliminary microscopic studies in animal samples treated
with IRE demonstrated minimal damage in extracellular structures as well as minimal
fibrotic or inflammatory margins.[65] In an osteosarcoma animal model, IRE generated increased peripheral T-lymphocytes
compared with surgical resection.[66] In a recent study employing an animal pancreatic cancer model, IRE exhibited a twofold
increase in CD3+ T cell infiltrates compared with cryoablation.[67]
In summary, non-hyperthermal ablation modalities such as cryoablation, IRE, and HIFU
appear to generate a more robust immune response compared with hyperthermal modalities,
possibly to the greatest degree with IRE. Regardless of ablative techniques, it is
clear that proinflammatory cytokines and the danger molecule signaling pathway are
activated in the immediate postablative period. The remaining and important question
is if this translates into a therapeutically immunogenic or prooncogenic environment
and which factors modulate the balance between them.
Investigating the postablation immune response is a challenging process. With varying
ablation devices, heterogeneous parameters and protocols at each center, and various
types of tumors treated, it is difficult to perform a standardized multicenter trial
or to compare studies across centers or countries. Investigations are further challenged
by the varying baseline individual immune function at the time of treatment. No optimal
time point for sampling or quantifying the immune response has been determined. Finally,
investigations may require additional invasive sampling of the treated area. Hence,
to date, most investigators have chosen to look at the systemic immune response based
on PBMCs as discussed earlier,[28]
[29]
[30]
[31] and immunopositron emission tomography has been investigated for the possible noninvasive
monitoring of immune response.[68]
[69]
Combination Therapy: Ablation and Immunotherapy
Combination Therapy: Ablation and Immunotherapy
It is established that a tumor-specific immune-stimulatory effect is generated after
image-guided locoregional ablation. However, given that this rarely translates into
robust effector clonal expansion or tumor killing, many recent studies have focused
on the introduction and testing of adjuvant immunotherapy combined with ablation to
synergistically shift the equilibrium out of inhibitory immune modulation ([Fig. 1]).
Ablation combined with immune checkpoint inhibitors has demonstrated a potential positive
synergistic effect on tumors elsewhere in the body in multiple studies ([Table 1]). In animal studies, the combination of anti-CTLA-4 and cryoablation[70] or anti-PD1 and RFA[71] slowed tumor growth and increased effector T cell infiltration of distant tumors.
In a pilot clinical study in 18 metastatic breast cancer patients, cryoablation combined
with anti-CTLA-4 (ipilimumab) revealed a sustained increase of IFN-γ, effector T cells,
and the ratio of effector T cells to regulatory T cells (Treg) in peripheral blood
samples.[72] In another pilot study,[73] 12 Barcelona clinic liver cancer stage C patients with metastatic HCC who failed
sorafenib treatment underwent percutaneous RFA and chemoablation therapy combined
with anti-CTLA-4 (tremelimumab). The investigators of that study reported that the
patients had 7.4 months median time to progression and 10.1 months median overall
survival without any severe treatment-related toxicity. The patients also had favorable
objective treatment responses with increased active CD8+ CTL infiltration in the distant
untreated lesion. Additionally, case reports have described the successful treatment
of colorectal lung metastasis using MWA/anti-PD-1 (pembrolizumab)[74] and metastatic clear cell RCC using cryoablation/anti-PD-1 (nivolumab) combinations.[75]
Table 1
Currently available human clinical data on the combination of immunomodulation and
ablation as of June 2019
|
Methods of immunomodulation
|
Studies
|
Phase
|
Immunomodulators
|
Ablative methods
|
Disease (no. of subjects)
|
Impact of combinatory therapy
|
|
Immune checkpoint inhibitors
|
McArthur et al[72]
|
I, II
|
Ipilimumab (anti-CTLA4)
|
Cryoablation
|
Breast cancer (19)
|
↑ IFN-γ, ↑ effector T cells,↑ effector T cells/regulatory T cells ratio in peripheral
blood
|
|
Duffy et al[73]
|
I, II
|
Tremelimumab (anti-CTLA4)
|
RFA + chemoablation
|
HCC (12)
|
7.4-mo median time to disease progression, 10.1-mo median overall survival, ↑ in-situ
CD8+ cells in treatment responders
|
|
Bäcklund and Freedman[74]
|
Case report
|
Pembrolizumab (anti-PD1)
|
MWA
|
Colorectal lung metastasis (1)
|
Complete response at 8 mo
|
|
Soule et al[75]
|
Case report
|
Nivolumab (anti-PD1)
|
Cryoablation
|
Renal cell carcinoma (1)
|
Decreased size and FDG uptake in osseous metastatic disease in 1 mo
|
|
Intratumoral injection of GM-CSF
|
Thakur et al[85]
|
I, II
|
GM-CSF
|
Cryoablation
|
Renal cell carcinoma (6)
|
↑ Tumor-specific IFN-γ (+) effector T cells, ↑ Th1/Th2 ratio in peripheral blood of
treatment responders
|
|
Si et al[86]
|
I, II
|
Prostate cancer (12)
|
↑ Tumor-specific effector T cells in peripheral blood
|
|
Adoptive transfer of activated allogenic immune cells
|
Niu et al[87]
|
Observational
|
GM-CSF stimulated allogenic DCs
|
Cryoablation
|
Pancreatic cancer (106)
|
↑ Median overall survival with combinatory treatment
|
|
Niu et al[88]
|
Observational
|
HCC (45)
|
↑ Median overall survival with combinatory treatment
|
|
Liang et al[90]
|
I, II
|
Stimulated allogenic NK cells
|
Cryoablation
|
Breast cancer (48)
|
↑ IFN-γ, ↑ effector T cells in peripheral blood with combinatory treatment
|
|
Lin et al[91]
|
I, II
|
Cryoablation
|
Renal cell cancer (60)
|
↑ Th1 cytokines, ↑ effector T cells in peripheral blood with combinatory treatment
|
|
Lin et al[92]
|
I, II
|
Cryoablation
|
NSCLC (60)
|
↑ Th1 cytokines, ↑ effector T cells in peripheral blood with combinatory treatment
|
|
Yang et al[93]
|
I, II
|
IRE
|
Primary liver cancer (40)
|
↑ Overall survival, ↑ progression-free survival, ↑ Th1 cytokines, ↑ effector T cells
in peripheral blood with combinatory treatment
|
Abbreviations: DCs, dendritic cells; FDG, fluorodeoxyglucose; GM-CSF, granulocyte-macrophage
colony-stimulating factor; HCC, hepatocellular carcinoma; IFN, interferon; IRE, irreversible
electroporation; MWA, microwave ablation; NK, natural killer; NSCLC, non-small cell
lung cancer; RFA, radiofrequency ablation.
Positive modulation of the antigen-presentation process by dendritic cells (DCs) has
been combined with ablation, showing promising results. In animal studies combining
intratumoral injection of activated DC with RFA[76] or cryoablation,[77] significant growth inhibition on distal untreated tumors and increased effector
immune cell infiltrates were demonstrated. Similarly, in animal studies combining
RFA or cryoablation with intratumoral stimulation of native DC by using toll-like
receptor (TLR) agonists,[78]
[79]
[80] OK-432,[81] granulocyte-macrophage colony-stimulating factor (GM-CSF),[82] krestin polysaccharide,[83] and BCG,[84] a favorable response in untreated tumor burden was demonstrated. Some of these preclinical
models were successfully reproduced in a few clinical studies. Thakur et al[85] and Si et al[86] confirmed robust tumor-specific CTL function in untreated tumors in patients with
metastatic RCC and prostate cancer when treated with cryoablation and GM-CSF injection.
Niu et al retrospectively reviewed 106 patients with metastatic pancreatic cancer[87] and demonstrated significantly improved median survival when cryoablation was combined
with adoptive transfer of GM-CSF stimulated DCs compared with cryoablation only, immunotherapy
only, or chemotherapy only (13, 7, 5, and 3.5 months, respectively). The authors applied
the same strategy in 45 patients with metastatic HCC,[88] revealing significantly improved overall survival with cryo-immunotherapy compared
with cryoablation only (32 vs. 17.5 months).[88]
NK cells are cytotoxic effector lymphocytes within the innate immune system. They
play an important role in cancer immune surveillance and are able to induce rapid
immune responses against malignant cells in an antigen-independent manner.[89] Adoptive transfer of allogenic NK cells has been combined with ablative therapies
in preclinical and clinical studies, demonstrating potential efficacy and safety.
In a pilot clinical study of cryoablation and NK cell therapy in 48 patients with
treatment-resistant metastatic breast cancer, increased immune effector T cells and
Th-1-type cytokines in the peripheral blood was demonstrated in the combinatory treatment
group (n = 16), although the increment in progression-free survival was not statistically
significant compared with the cryoablation-only group (n = 16).[90] Of note, this study also included a triple-combination group (n = 16, cryoablation, allogenic NK cells, trastuzumab) demonstrating a significant
increase in immune response and progression-free survival compared with the aforementioned
two groups. Two prospective clinical studies combining cryoablation with allogenic
NK cell immunotherapy of metastatic RCC (n = 60)[91] and non-small cell lung cancer (n = 60)[92] also revealed enhanced effector immune cell quantity as well as Th-1–type cytokines
in the peripheral blood. However, these studies did not report any clinical outcomes
regarding progression-free survival or regression of distant untreated tumor. Lastly,
one study using a combination of IRE and allogenic NK cell therapy for primary liver
cancer patients demonstrated survival benefits and increased immune response compared
with IRE therapy only.[93]
Future Directions
As of June 2019, there are 22 ongoing or planned clinical trials for various combinatory
regimens of locoregional ablative therapy and immunotherapy registered in the clinicaltrials.gov database ([Table 2]). Additionally, there are also trials investigating the efficacy and safety of immunotherapy
combined with other locoregional IO therapies such as chemoembolization or radioembolization.
In addition to these preliminary outcome-based studies, there are many important questions
to be answered.[94] Most importantly, the timing, sequence, number, and type of combinatory therapy
should be determined to optimize the synergistic efficacy.
Table 2
Locoregional ablative therapy combined with immunotherapy: ongoing and planned registered
trials as of June 2019
|
Trial no.
|
Ablative modality
|
Immunotherapy
|
Disease (no. of subjects)
|
Phase
|
Expected study completion dates (mm/yyyy)
|
|
NCT02851784
|
MWA
|
CIK cells
|
Hepatocellular carcinoma (50)
|
II, III
|
12/2017
|
|
NCT03101475
|
SBRT or RFA
|
Durvalumab (anti-PDL1) + Tremelimumab (anti-CTLA4)
|
Colorectal liver metastasis (70)
|
II
|
01/2023
|
|
NCT03695835
|
Cryoablation or RFA
|
Anti-PD1 + anti-CTLA4 + GM-CSF
|
Prostate adenocarcinoma (18)
|
Observational
|
12/2025
|
|
NCT03864211
|
MWA or RFA
|
Toriplimab (anti-PD1)
|
Hepatocellular carcinoma (120)
|
I, II
|
03/2021
|
|
NCT03753659
|
MWA or RFA
|
Pembrolizumab (anit-PD1)
|
Hepatocellular carcinoma (30)
|
II
|
09/2022
|
|
NCT02678013
|
RFA
|
CIK cells
|
Hepatocellular carcinoma (210)
|
III
|
01/2022
|
|
NCT02849366
|
Cryoablation
|
NK cells
|
Soft-tissue sarcoma (30)
|
I, II
|
07/2019
|
|
NCT02849379
|
Cryoablation
|
NK cells
|
Tongue cancer (30)
|
I, II
|
07/2019
|
|
NCT02849353
|
Cryoablation
|
NK cells
|
Ovarian cancer (30)
|
I, II
|
07/2019
|
|
NCT02849340
|
Cryoablation
|
NK cells
|
Cervical cancer (30)
|
I, II
|
07/2019
|
|
NCT02849314
|
Cryoablation
|
NK cells
|
Laryngeal cancer (30)
|
I, II
|
07/2019
|
|
NCT02849327
|
Cryoablation
|
NK cells
|
Hepatic metastatic disease (30)
|
I, II
|
07/2019
|
|
NCT02844335
|
Cryoablation
|
NK cells
|
Breast cancer (30)
|
I, II
|
07/2019
|
|
NCT02843607
|
Cryoablation
|
NK cells
|
Renal cell carcinoma (30)
|
I, II
|
07/2019
|
|
NCT02843815
|
Cryoablation
|
NK cells
|
Non-small cell lung cancer (30)
|
I, II
|
07/2019
|
|
NCT02849015
|
Cryoablation
|
NK cells
|
Primary liver tumor (10)
|
I, II
|
07/2018
|
|
NCT01853618
|
Cryoablation or RFA or TACE
|
Tremelimumab (anti-CTLA4)
|
Primary liver tumor (61)
|
I, II
|
12/2020
|
|
NCT03008343
|
IRE
|
NK cells
|
Primary liver tumor (20)
|
I, II
|
12/2019
|
|
NCT00891475
|
RFA
|
Sunitinib (tyrosine kinase inhibitor) or IFN-α
|
Renal cell carcinoma (114)
|
I, II
|
01/2011
|
|
NCT03949153
|
Cryoablation
|
Ipilimumab (anti-CTLA4)
|
Cutaneous melanoma (15)
|
I, II
|
12/2021
|
|
NCT03939975
|
RFA or MWA
|
Pembrolizumab or nivolumab or JS001 (anti-PD1)
|
Hepatocellular carcinoma (50)
|
II
|
05/2023
|
|
NCT03237572
|
HIFU
|
Pembrolizumab (anti-PD1)
|
Breast cancer (15)
|
I
|
11/2021
|
Abbreviations: CIK, cytokine-induced killer; HIFU, high intensity focused ultrasound;
IFN, interferon; IRE, irreversible electroporation; MWA, microwave ablation; NK, natural
killer; RFA, radiofrequency ablation; TACE, transarterial chemoembolization.
There is a great potential in the combination of locoregional therapy and immunotherapy.
The synergy between interventional radiology and immunooncology with their different
philosophies and approaches will enhance our understanding of cancer biology in general.
Many innovative, minimally invasive locoregional IO therapies have been developed,
demonstrating similar safety and efficacy profiles between them albeit the great heterogeneity
in techniques and application. Further understanding of the tumor immune microenvironment
may also shed light on mechanisms to differentiate and tailor IO therapies toward
more personalized cancer therapy.
Conclusion
Locoregional tumor ablative techniques induce tumor-derived immunogenic activation
at local and systemic levels, which may ultimately translate into beneficial therapeutic
effects in local and remote tumors. To overcome the body's innate negative immune
modulation in the cancer-immunity cycle and to optimize the immunogenic response,
ablative therapy has been combined with various immunotherapy regimens, resulting
in promising outcomes, although these findings remain preliminary. Understanding the
tumor microenvironment will help advance our knowledge of existing IO procedures,
as well as aid in the development of innovative, personalized oncologic care.
