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Review

Abscopal Effect with Liver-Directed Therapy: A Review of the Current Literature and Future Directions

by
Jonah M. Levine
1,
Alyssar Habib
2,
Mikhail Silk
3,
Greg D. Sacks
1,
Rafael Winograd
4,
Colin S. Hill
5,
Ammar A. Javed
1,
Christopher L. Wolfgang
1 and
D. Brock Hewitt
1,*
1
Department of Surgery, The NYU Grossman School of Medicine and NYU Langone Health, New York, NY 10016, USA
2
Department of Medicine, The NYU Grossman School of Medicine and NYU Langone Health, New York, NY 10016, USA
3
Department of Vascular and Interventional Radiology, The NYU Grossman School of Medicine and NYU Langone Health, New York, NY 10016, USA
4
Department of Medical Oncology, The NYU Grossman School of Medicine and NYU Langone Health, New York, NY 10016, USA
5
Department of Radiation Oncology, The NYU Grossman School of Medicine and NYU Langone Health, New York, NY 10016, USA
*
Author to whom correspondence should be addressed.
Livers 2024, 4(4), 601-614; https://doi.org/10.3390/livers4040042
Submission received: 28 August 2024 / Revised: 23 October 2024 / Accepted: 11 November 2024 / Published: 22 November 2024
Browse Figures
Figure 1
<p>Schematic illustration of histotripsy: (<b>a</b>) technical setup of histotripsy; (<b>b</b>) real-time evaluation of treatment; pink dashed circle shows larger region of treatment, white dashed circle shows center of treatment where the hyperechoic region is due to the presence of bubbles (<b>c</b>) post-treatment visualization; white dashed circle shows hypoechoic region due to liquification (<b>d</b>) liquified region of the organ; (<b>e</b>) histology [<a href="#B12-livers-04-00042" class="html-bibr">12</a>].</p> "> Figure 2
<p>Treatment of targeted tumor and mechanism of distant control. The figure on the left shows how a targeted tumor (pink) can cause a systemic effect leading to a reduction in distant tumors (red) [<a href="#B63-livers-04-00042" class="html-bibr">63</a>].</p> "> Figure 3
<p>Proposed mechanisms for the immune activation of histotripsy [<a href="#B63-livers-04-00042" class="html-bibr">63</a>].</p> ">
Versions Notes

Abstract

:
The liver is a common site for metastatic disease. In select patients with isolated liver metastases, surgical resection improves survival and may be potentially curative in patients with favorable “tumor biology”. However, when surgical resection is not feasible, liver-directed therapies (LDTs) can also improve outcomes, including survival, in the appropriate clinical situations. LDTs, including hepatic artery infusion, radioembolization, radiation, and ablation techniques, such as thermal ablation and histotripsy, offer local control and potential systemic effects, including the abscopal effect. The abscopal effect occurs when nontargeted, nontreated tumors regress following localized therapy to other tumors. Preclinical and clinical studies suggest that antigen-induced upregulation of key immune regulators plays a central role in this process. Unfortunately, clinical reports of the abscopal effect following LDT are exceedingly rare. However, histotripsy, a noninvasive, nonionizing, and nonthermal ablation technique, may induce an abscopal effect more frequently and robustly than other LDTs. Histotripsy enhances tumor immunogenicity through precise acoustic cavitation that better preserves the local tissue architecture while increasing antigen release, resulting in a robust local and systemic immune response. Ongoing trials are investigating these immunogenic mechanisms and the ability to generate an abscopal effect more reliably with adjuncts such as checkpoint inhibitors. This work has significant implications regarding the management of patients with liver metastasis.

1. Introduction

The liver is a common site of metastatic disease, especially for cancers arising from the gastrointestinal tract, due to the liver’s rich dual blood supply and immune-tolerant microenvironment [1,2]. Aggressive management of oligometastatic disease in select patients with favorable disease biology has improved patient survival in colorectal cancer and neuroendocrine tumors, among others [3,4]. Surgical resection, transplant, and, for smaller lesions, thermal ablation or radiation are curative-intent strategies for liver metastases [5,6]. However, aside from liver transplant, these treatment modalities have diminishing returns with increasing disease burden due, in part, to concerns with the functional liver remnant. Conversely, in patients where curative intent therapy is not possible due to the extent of liver disease, other methods of treatment must be utilized for disease control. In these instances, liver-directed therapy (LDT) and systemic therapy (e.g., chemotherapy, immunotherapy, targeted therapy) become the primary treatment modalities. LDTs include hepatic artery infusion, yttrium-90 (Y-90) trans-arterial radioembolization (TARE), trans-arterial chemoembolization (TACE), transarterial bland embolization (TAE), radiation therapy (e.g., stereotactic body radiation therapy [SBRT]), and most recently, histotripsy [7,8,9,10,11].
Histotripsy is a noninvasive (i.e., transcutaneous), nonionizing, and nonthermal ablation technique that uses focused ultrasound to mechanically destroy tissue, leaving behind an acellular lysate through a process called acoustic cavitation. Developed in the early 2000s, the process involves applying focused ultrasound to deliver high-amplitude, short-duration ultrasound pulses, usually microseconds to milliseconds, to a target area. These pulses generate a high-pressure environment, creating micro-bubbles that rapidly expand and contract through a phenomenon called acoustic cavitation, imparting mechanical forces on the surrounding cells. The resulting acellular lysate is absorbed over time, leaving a minimal remnant scar. The treatment is observed in real-time with ultrasound, allowing for parameter adjustments as needed (Figure 1) [12]. The histotripsy ablation zone avoids damage to non-targeted tissue, preserving collagenous vessels and ducts [13].
When curative-intent therapy is not possible, LDTs are implemented to improve local disease control. However, in rare instances, lesions not directly targeted by LDT have demonstrated radiographic response in the absence of other therapies (e.g., systemic therapy). Mole et al. first described the abscopal effect in 1953 following their experiments investigating radiotherapy (RT) in mice as “an action at a distance from the irradiated volume within the same organism” [14]. In subsequent decades, the abscopal effect has been observed following local therapy, primarily RT, in multiple different cancer types, but the event rate is exceedingly low, with few documented cases over the last 70 years [15]. Recently, studies have suggested that histotripsy may more frequently and robustly induce an abscopal effect [16]. This review explores the evidence supporting an abscopal effect following local treatment of liver tumors with particular attention to histotripsy technology. By examining existing preclinical and clinical evidence, we aim to explore new pathways for combination therapies, integrating local and systemic approaches to treat patients with metastatic liver disease.

2. Abscopal Effect and Liver-Directed Therapy

The abscopal effect is understudied, with very few reports of the phenomenon in the literature. The phenomenon describes the partial or complete regression of lesions outside the treatment field not attributed to systemic therapy. Most instances occur in immunogenic tumors such as renal cell carcinoma, melanoma, and lung cancer following RT; however, the abscopal effect has been reported in other, traditionally less-immunogenic tumors such as breast and pancreatic cancer [17,18,19].
LDT has shown promise in local tumor control and in eliciting the abscopal effect, as evidenced by several preclinical studies and case reports that have reported this phenomenon, highlighting its potential to enhance overall cancer treatment outcomes [4,7,8,9]. RT has become one of the most common and important tools at our disposal in cancer treatment and is an integral part of the treatment of both primary liver lesions and liver metastases [20]. RT destroys DNA directly, causing double-strand breaks, and indirectly by creating free radicals, which then cause single-strand breaks. Cancer cells are most susceptible as they proliferate at a higher-than-normal rate and cannot repair themselves as well as normal cells [21,22,23]. While the primary intent of RT is local control, RT was the first modality to demonstrate an abscopal effect [14]. Drs. Everson and Cole further reported on the spontaneous regression of tumors in a 1956 review article. The authors described 47 cases of spontaneous tumor regression at a distant site in the absence of therapy or following therapy considered inadequate to influence such a regression response [24]. While many of these early papers were purely descriptive, more recent preclinical and clinical studies have revealed some underlying mechanisms of how LDT may induce an abscopal effect [25].

2.1. Preclinical Studies

Early studies investigating the abscopal effect demonstrate upregulation of the patient’s immune response [26,27,28]. For example, when radiation is used to treat a tumor, the ensuing destruction of the tumor cells releases tumor antigen, causing a cascade of events that lead to the creation of tumor-specific antibodies [29]. Specifically, destroyed tumor cells release a group of molecules called danger-associated molecular patterns (DAMPs). These DAMPs then interact with antigen-presenting cells (APCs), such as dendritic cells, that, in turn, cause activation of cytotoxic T lymphocytes, mediators of the adaptive immune response [30,31]. Preclinical models suggest that RT enhances APC-cytotoxic T lymphocyte interactions, upregulates major histocompatibility complex (MHC) class I, and increases antigen presentation and cytotoxic T lymphocyte recognition of irradiated cells [27].
One of the earliest preclinical experiments explored the abscopal effect using a syngeneic fibrosarcoma mouse model [32]. Stone et al. found that the radiation dose required to achieve a 50% reduction in primary tumor size was notably lower in T cell-competent mice compared to T cell-depleted mice. T cell-competent mice also showed regression of distant metastases at a higher rate compared to depleted mice [32]. This provided evidence of T cell response being an important mediator of the abscopal effect. Other preclinical studies of RT in murine models have shown similar findings. In a study by Camphausen et al., the investigators found that the abscopal effect against Lewis lung carcinoma, a highly aggressive cancer originally derived from a lung tumor of a C57BL mouse, was more prominent in wild-type p53 mice compared to p53 knockout mice. This finding suggests that p53 is also a key mediator in the abscopal effect following RT [33]. While these preclinical studies did not specifically utilize LDT, they provide evidence of the abscopal effect following RT [34]. Research investigating immune checkpoint blockade has also helped elucidate the biological mechanisms responsible for the abscopal effect. Immune checkpoint proteins such as programmed cell death-1 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) guard against autoimmunity, suppressing the immune system. These proteins are expressed by tumor suppressor cells such as CD4+ T lymphocytes, CD8+ T lymphocytes, dendritic cells, and natural killer cells. Their activation results in an “off” switch for the cell, preventing cellular expansion and decreasing immune cell function. Immune checkpoint inhibitors (ICIs) block the activation of these checkpoints, leaving the cell “on” to fight cancer cells [35]. ICIs may work synergistically with LDT to activate the immune system and destroy tumor cells. Two specific ICIs of interest recently are anti-PD-1 and anti-CTLA-4. Anti-PD-1 works on newly activated and exhausted T cells, while anti-CTLA-4 works on naïve and regulatory T cells. Both ICIs have been shown to enhance the abscopal effect with local therapy [36,37,38,39,40]. Preclinical studies have supported this immune system activation via anti-CTLA-4 and anti-PD-1 in consort with RT [41,42]. These studies demonstrate the significance of ICIs in enhancing the abscopal effect and support additional investigation to elucidate the clinical impact of combination therapy.

2.2. Clinical Studies

While the clinical evidence supporting an abscopal effect following LDT primarily consists of case reports (Table 1), these studies suggest that CD8+ cytotoxic T lymphocytes play a critical role in driving the abscopal effect. Three retrospective studies have shown that increased CD8+ CTL infiltration and decreased CD4+ FoxP3+ regulatory T cells (Tregs) are associated with abscopal tumor regression [43,44,45]. For example, Lock et al. described the case of a 71-year-old male with biopsy-proven multifocal, metastatic hepatocellular carcinoma to the lung—T3N0M1 [46]. Based on the patient’s poor performance status and extent of disease, he received RT without any adjuvant chemotherapy or immunotherapy. The patient underwent 70 Gy treatment in 15 fractions to the liver. Two months after the treatment, a restaging CT scan was conducted, and the largest liver lesion, measured initially at 14 cm, had shrunk to around 3 cm, showing a response in the liver. The alpha-fetoprotein levels also decreased during this time. At the four-month follow-up CT scan, the liver lesions were stable, but interestingly, there was almost a complete response of the pulmonary metastases that the RT had not targeted [46].
The abscopal effect has also been shown in patients who underwent Y-90. In one instance, Ghodadra et al. report a case of an 80-year-old male with squamous cell carcinoma of the skin who developed hepatic metastases while on systemic therapy [47]. The patient received multiagent systemic therapy for 18 months but had disease progression with the development of liver metastases. The patient was treated with selective Y90 through the anterior branch of the right hepatic artery, targeting disease in segments V and VII, leaving the disease in segment IVB untreated. Imaging three months following Y90 showed a response in the targeted segments of the liver and a complete response of the nontargeted lesion in segment IVB [48].
A few case reports have shown that combining RT and immunotherapy induces the abscopal effect. In one such report, a 57-year-old man diagnosed with metastatic melanoma received treatment combining two cycles of ipilimumab, a monoclonal antibody that binds to CTLA-4, followed by SBRT to two out of seven liver metastases and two additional cycles of ipilimumab. Interestingly, in this patient, unlike previous reports, ipilimumab was used specifically to induce an anti-tumor immune response and enhance a possible abscopal effect. After the last two cycles of ipilimumab, a hypermetabolic lesion in the left arm and all lesions in the liver were completely resolved [49]. Furthermore, at 6.5 years post-treatment, the patient remained in complete remission with no signs of disease recurrence, showing that sustained remission is possible following such a dramatic response [50].
Finally, Golden et al. described the first case of an abscopal effect in treatment-refractory lung cancer. A 64-year-old male diagnosed with metastatic lung adenocarcinoma to the liver received chemotherapy as well as RT but developed disease progression after one year of therapy with new metastasis found in the liver, bony pelvis, thoracolumbar spine, and right humerus. He received salvage ipilimumab and RT to one of the liver lesions. Post-treatment, the patient developed an increase in tumor-infiltrating cytotoxic lymphocytes, normalization of tumor markers, and regression of all disease, remaining without evidence of disease one year following treatment [51].

3. Histotripsy and the Immune Response

Histotripsy is a noninvasive, nonionizing, and nonthermal ablation technique approved by the FDA in October 2023 for the treatment of primary or secondary liver tumors [16,52]. The safety and efficacy endpoints were met in the THERESA and #HOPE4LIVER phase I/II trials [53,54]. Clinical and pre-clinical trials are ongoing to investigate histotripsy’s safety and efficacy in treating disease in other organ sites (e.g., kidney, prostate, pancreas, heart) and conditions (e.g., thrombosis, kidney stones, biofilms) (Table 2) [54]. Histotripsy uses short-duration, high-negative-pressure focused ultrasound pulses to create microbubbles that mechanically destroy tissue through a process of rapid expansion and collapse called acoustic cavitation [55]. The acoustic cavitation process results in an acellular homogenate that reabsorbs over time [56]. The short ultrasound bursts with a low-duty cycle minimize heat generation. Lower absolute temperatures and the reliance on mechanical destruction instead of thermal destruction limits the heat sink effect, resulting in a homogenous treatment zone with more precise and predictable treatment margins. Furthermore, histotripsy is associated with fewer off-target effects than thermal ablation, with greater preservation of bile ducts and blood vessels [57].
Early trials demonstrate promising results with histotripsy as an LDT. In the first preclinical study, Worlikar et al. showed that histotripsy treatment of human-derived HCC in rodents resulted in complete tumor tissue fractionation, reduced tumor volumes on post-treatment MRI, and improved overall survival [58]. Subsequent preclinical studies by Worlikar et al. evaluating histotripsy efficacy and safety demonstrate acceptable safety profiles and complete tumor regression when targeting tumors through the chest and abdominal wall [59]. In the THERESA study, a first-in-human, multicenter phase I trial, histotripsy was performed on 11 tumors in 8 patients with unresectable end-stage liver tumors. The primary endpoint of acute technical success was met in all procedures with no device-related adverse events. Interestingly, two patients demonstrated a decline in tumor markers during the two months following the procedure [54]. A larger multi-national phase I/II clinical trial, #HOPE4LIVER, evaluated histotripsy therapy for 44 tumors in 40 patients. Early data show a 95.5% technical success rate, with only three complications (6.8%) [60,61].

Histotripsy and the Abscopal Effect

While the intention of treatment is local destruction, early clinical experience suggests more frequent abscopal effects compared to other LDTs (Figure 2) [16,61]. One documented case is of a 67-year-old male patient who had stage 4 colon cancer with synchronous hepatic metastases [62]. After curative-intent surgery, he developed recurrent liver and lung metastases three years later. He received combined chemotherapy + immunotherapy and thermal ablation, but his disease progressed. He was eventually enrolled in the THERESA study and received histotripsy to a single liver lesion. Within one week of the procedure, his CEA decreased to half. Interval imaging over the following two months showed a decrease in the size of the treated lesion as well as numerous other nontreated liver lesions [62].
Livers 04 00042 g002
Figure 2. Treatment of targeted tumor and mechanism of distant control. The figure on the left shows how a targeted tumor (pink) can cause a systemic effect leading to a reduction in distant tumors (red) [63].
Figure 2. Treatment of targeted tumor and mechanism of distant control. The figure on the left shows how a targeted tumor (pink) can cause a systemic effect leading to a reduction in distant tumors (red) [63].
Livers 04 00042 g002
Table 1. Case reports of liver directed therapy leading to an abscopal effect at a distant site.
Table 1. Case reports of liver directed therapy leading to an abscopal effect at a distant site.
Primary TumorStudyAgeGenderTreatmentTechniqueAbscopal Effect Location
HCCLock et al. [46]71MRadiation70 Gy treatment in 15 fractionsPulmonary metastasis
Breast cancer
(PR +, ER +, HER2−)		Powerski et al. [47]43FRadioembolizationSequential Yittrium-90 (Y-90) radioembolizationUntreated liver lesions
Squamous cell lung carcinomaGhodadra et al. [48]80MRadioembolizationYttrium-90 radioembolization therapyLeft hepatic lobe lesions
Metastatic MelanomaGutkin et al. [50]57MRadiation + ImmunotherapyStereotactic body radiotherapy + two cycles of ipilimumabLeft arm and all untreated lesions in the liver
Non-small cell lung cancerGolden et al. [51]64MRadiation + Immunotherapy30 Gy distributed over 5 fractions
3 more cycles of ipilimumab, 3 mg/Kg body weight		Non irradiated liver metastases resolved as well as osseous metastases
Colorectal adenocarcinomaVidal-Jove et al. [62]67MHistotripsy HistotripsyHepatic metastases
Table 2. Current clinical trials on histotripsy.
Table 2. Current clinical trials on histotripsy.
SponsorNameLocationActive (Y/N)Recruitment Status (Y/N)Organ System FocusDesign DetailsClinical Trial Number
HistoSonics, Inc.GANNONUKYYPancreasProspective, multi-center, single-arm, pilot trial.NCT05432232
HistoSonics, Inc.CAINSpainYNot yetRenalProspective multi-center, single-arm, feasibility trialNCT06282809
HistoSonics, Inc.#HOPE4KIDNEYUSA (CT, FL, MD, NY, OH, WA)YYRenalProspective, multi-center, single-armNCT05820087
HistoSonics, Inc.#HOPE4LIVER USUSA (FL, IL)YCompleteLiverProspective, multi-center, single-arm, non-randomizedNCT04572633
HistoSonics, Inc.#HOPE4LIVER EU/UKGermany (2), Italy, Spain, UK (2)YCompleteLiverProspective single-arm, non-randomized trialNCT04573881
HistoSonics, Inc.BOOMBOX: Master StudyTBDYNot YetLiverProspective, observational, single arm, non-randomized, prospective master studyNCT06486454
Recent studies have explored possible mechanisms to explain the abscopal effect following histotripsy. In a study by Qu et al., mice with melanoma or hepatocellular tumors were treated with histotripsy, thermal ablation, RT, or CTLA-4 checkpoint inhibition [64]. Histotripsy caused the release of tumor antigens with retained immunogenicity, stimulating local intratumoral infiltration of innate and adaptive immune cell populations at a magnitude greater than RT or thermal ablation. This increased stimulation of immune cells may be due to the difference in tissue destruction between RT, thermal ablation, and histotripsy. Thermal ablation and RT lead to cell death via heat-denaturation and necrosis. However, histotripsy causes cell death through a nonthermal mechanism that preserves some subcellular components and more surrounding tissue architecture. This process may generate more targetable antigens and preserve more microenvironment, allowing for an increased immunogenic response [64]. Furthermore, the authors found that histotripsy promoted abscopal immune responses at untreated tumor sites (i.e., pulmonary metastases), an effect potentiated with ICI therapy. The immune response was mediated through histotripsy-induced translocation of calreticulin to the cellular membrane and the local and systemic release of DAMPs, specifically high-mobility group box protein 1 (Figure 3) [64,65,66]. Investigating combinational therapy has continued to be one of the most promising avenues for cancer treatment with histotripsy and enhancing an abscopal effect at distant sites. Another study investigating histotripsy and immune checkpoint blockade in murine models showed that utilizing histotripsy with an anti-CD40 agonist antibody in combination with ICIs against CTLA-4 and PD-L1 decreased the size of distant tumors and increased survival in mice [67].
Cytokines are another important immune system regulator that histotripsy may modulate, most prominently IFN-γ. IFN-γ is an important cytokine that induces the production of multiple proteins involved in the MHC class I and II antigen-presenting pathways. Multiple studies have shown an increase in IFN-γ after histotripsy treatment [64,68,69]. This increase in IFN-γ can help promote ischemia and lead to activation of the apoptotic pathway [70]. More importantly, IFN-γ improves T cell function through promoting surface MHC class I expression, as well as upregulating the activity of CD8 cytotoxic T cells. This antitumor response from IFN-γ helps induce the abscopal effect.
Histotripsy is a promising treatment for the definitive management of local tumors and its potential ability to sensitize tumors to adaptive immunity. Histotripsy has the ability to increase tumor immunogenicity by releasing DAMPs following mechanical cellular disruption, which are then recognized TLRs, specifically dendritic cells and macrophages, which, in turn, trigger an adjuvant effect and enhance antigen presentation and stimulate T lymphocytes. This pathway is likely a significant mechanism in the abscopal effect. In contrast to existing ablative techniques such as microwave ablation (MWA), the more precise ablative margins and limited heat denaturation preserve the neighboring vascular and lymphatic architecture, improving lymphocyte access to the tumor microenvironment [63].

4. Summary

An aspiration of cancer treatment is the ability to definitively treat a tumor with minimal side effects while increasing tumor immunogenicity to enhance local and systemic responses. Especially as systemic immunotherapy plays an increasingly important role in the management of solid tumors, interventions that may augment these therapies or overcome resistance mechanisms are of great clinical interest. Definitive therapies have become less invasive with minimally invasive surgery (i.e., laparoscopic or robotic surgery) and transcutaneous ablation techniques. Histotripsy is another level of progression in this regard, given the completely noninvasive approach; however, patients still require intubation and paralysis to limit movement during treatment.
Although data are limited, studies suggest that the most robust abscopal response for patients with liver metastases is seen when combining LDT with immunotherapy. Preclinical studies have begun investigating how to augment therapies such as histotripsy to induce an abscopal effect. In a 2024 study by Wu et al., the authors evaluated combination therapy with MWA, IL-21, and anti-PD-1 monoclonal antibodies for treating colon cancer in mouse models [71]. MWA upregulated the expression of IL-21 on immune cells in untreated tumors. The combination of MWA and IL-21 induced a robust anti-tumor response by enhancing the effector function of CD8+ T cells and promoting dendritic cell maturation and antigen presentation in untreated tumors. Of note, this combined effect was contingent upon T-cell circulation. Finally, combining all three therapies generated the most profound abscopal effect.
Kemmotsu et al. described an interesting method of augmenting therapy to generate an abscopal effect [72]. They used hydrogen peroxide to induce oxidative stress and cytotoxicity. Mice with two tumors received an intratumor injection with hydrogen peroxide followed by RT to a single lesion, while the second lesion remained untreated. Single-agent intervention with hydrogen peroxide or RT did not reduce tumor growth. However, combined therapy significantly reduced tumor growth of the nontreated lesion. After combined therapy, increased concentrations of dendritic cells and CD8+ T cells were present in the nontreated tumors. Finally, PD-1 blockade further potentiated the abscopal effect with combined treatment [72]. In humans, Golden et al. investigated the utility of granulocyte-macrophage colony-stimulating factor (GM-CSF), a potent promoter of dendritic cell maturation, to augment local RT and induce an abscopal response in 41 patients with progressing metastatic cancer [73]. Patients received RT at 35 Gy in ten fractions over two weeks and daily subcutaneous injections of GM-CSF during the second week. The investigators observed an abscopal response (i.e., a decrease in the size of an untreated tumor) in 11 (26.8%) out of the 41 patients, with only one serious grade 4 event (pulmonary embolism). Although this study did not include patients with liver lesions, it showed that the combination of RT and GM-CSF can induce an abscopal response in humans.
Additionally, mouse model studies have shown that combining histotripsy with other mainstay treatments such as immunotherapy, chemotherapy, or RT has the potential to enhance effectiveness via the abscopal effect. For example, immunotherapies like CTLA-4 and PD-1 inhibitors rely on a pro-inflammatory state rich in tumor-immune cell interactions. Histotripsy creates an immunogenic environment with DAMPs, cytokines, and chemokines, transforming the tumor microenvironment into a pro-inflammatory state and potentially enhancing these therapies’ effectiveness. Preclinical studies by Qu et al. and Singh et al. have demonstrated how CTLA-4 and PD-1 blockade can enhance the abscopal effect and lead to an induced systemic immune upregulation [64,67].

5. Future Directions

As histotripsy is a relatively new technology, many questions remain unanswered. For example, does the timing and sequencing of histotripsy with other therapies impact efficacy? Does resection of the primary disease play a role? A recent study demonstrated the crucial role of preserving tumor-draining lymph nodes. Fransen et al. found that the immune-mediated response was greater in mice receiving immunotherapy before disruption of the tumor-draining lymph nodes [74]. Interestingly, disruption of contralateral lymph nodes had no impact on ICI-induced immune activation. Studies have looked at this in RT therapy and have found that innovative combinations of RT with immunotherapy, cancer vaccines, and cytokines help induce strong immune responses and, in some cases, an abscopal effect. Preclinical studies have shown that the administration of cancer vaccines or chimeric antigen receptor T cells after RT improves tumor response [75,76]. The synergistic action of immunotherapy with histotripsy has been described, but the ideal sequencing of these therapies remains unknown.
Monitoring the abscopal effect and determining whether there has been a response is also an important question for future investigation. A recent study showed that the combination of LDT with immunotherapy can lead to the downstaging of hepatocellular carcinoma and eventually resection. This study by Raj et al. utilized ctDNA levels to monitor treatment response, showing which patients were disease free. This method could be utilized more broadly to monitor patients’ response to combination therapies with histotripsy in addition to cross-sectional imaging [77].
Studies investigating histotripsy and its ability to induce an abscopal effect have laid the groundwork for clinical trials. Currently, multiple clinical trials to investigate histotripsy as a primary or adjunctive treatment for cancer are ongoing or will start soon. The mature #HOPE4LIVER data were recently published and show promising results. This trial demonstrated a 95% technical success rate defined as “tumor treatment volume being greater than or equal to the targeted volume with complete tumor coverage”, which compared similarly to other established local treatments. Importantly, there was only a 7% major complication rate, which, again, is within the normal range for similar treatments [78]. These preliminary data give strong evidence towards the safety and efficacy of histotripsy for LDT but do not yet answer important questions about distant tumor regression and overall survival.
The BOOMBOX trial is an observational, single-arm, non-randomized, prospective master study to evaluate outcomes in a real-world setting. The CAIN trial, named after the coinventor of histotripsy, investigates the use of histotripsy to treat renal tumors. Histotripsy is safe and effective in preclinical studies of the kidney; however, this will be the first-in-human trial [79]. Pancreatic cancer has also been a focus of preclinical studies for histotripsy, as it is one of the most challenging types of cancer to treat. Studies with animal models have established that histotripsy is well tolerated in pancreatic cancer treatment, making it feasible for human trials [80]. The GANNON trial has now begun recruiting to evaluate histotripsy in patients with advanced pancreatic cancer. These trials will be very informative with respect to the efficacy and safety of histotripsy in other tumors.

6. Conclusions

The abscopal effect represents a fascinating and incompletely understood phenomenon in oncology. Localized treatments provide definitive therapy to a targeted lesion and may elicit a systemic anti-tumor response, resulting in clinical improvement of non-targeted lesions. Since the abscopal effect was first described over 70 years ago, reported cases are limited and primarily associated with RT. However, the advent of histotripsy shows promise in providing precise local tumor control and potentially inducing more frequent and robust systemic responses. Preclinical studies suggest that histotripsy may trigger stronger immune responses and upregulate key immune mediators more effectively than other LDTs. Histotripsy holds the potential to significantly impact the treatment landscape for primary and metastatic disease by harnessing and amplifying the abscopal effect. In addition, combining histotripsy with other treatments, such as immunotherapy, may potentiate the abscopal effect, offering new hope to improve patient outcomes through combination therapies that integrate local and systemic modalities. Prospective data from ongoing and future clinical trials will be key to guiding the integration of this treatment modality into clinical practice.

Author Contributions

Conceptualization, D.B.H. and J.M.L.; Writing—Original Draft Preparation, J.M.L., A.H. and D.B.H.; Writing—Review and Editing, A.A.J., C.L.W., M.S., G.D.S., R.W., C.S.H. and D.B.H.; Supervision, A.A.J., D.B.H. and C.L.W. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

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Livers 04 00042 g001
Figure 1. Schematic illustration of histotripsy: (a) technical setup of histotripsy; (b) real-time evaluation of treatment; pink dashed circle shows larger region of treatment, white dashed circle shows center of treatment where the hyperechoic region is due to the presence of bubbles (c) post-treatment visualization; white dashed circle shows hypoechoic region due to liquification (d) liquified region of the organ; (e) histology [12].
Figure 1. Schematic illustration of histotripsy: (a) technical setup of histotripsy; (b) real-time evaluation of treatment; pink dashed circle shows larger region of treatment, white dashed circle shows center of treatment where the hyperechoic region is due to the presence of bubbles (c) post-treatment visualization; white dashed circle shows hypoechoic region due to liquification (d) liquified region of the organ; (e) histology [12].
Livers 04 00042 g001
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Figure 3. Proposed mechanisms for the immune activation of histotripsy [63].
Figure 3. Proposed mechanisms for the immune activation of histotripsy [63].
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Levine, J.M.; Habib, A.; Silk, M.; Sacks, G.D.; Winograd, R.; Hill, C.S.; Javed, A.A.; Wolfgang, C.L.; Hewitt, D.B. Abscopal Effect with Liver-Directed Therapy: A Review of the Current Literature and Future Directions. Livers 2024, 4, 601-614. https://doi.org/10.3390/livers4040042

AMA Style

Levine JM, Habib A, Silk M, Sacks GD, Winograd R, Hill CS, Javed AA, Wolfgang CL, Hewitt DB. Abscopal Effect with Liver-Directed Therapy: A Review of the Current Literature and Future Directions. Livers. 2024; 4(4):601-614. https://doi.org/10.3390/livers4040042

Chicago/Turabian Style

Levine, Jonah M., Alyssar Habib, Mikhail Silk, Greg D. Sacks, Rafael Winograd, Colin S. Hill, Ammar A. Javed, Christopher L. Wolfgang, and D. Brock Hewitt. 2024. "Abscopal Effect with Liver-Directed Therapy: A Review of the Current Literature and Future Directions" Livers 4, no. 4: 601-614. https://doi.org/10.3390/livers4040042

APA Style

Levine, J. M., Habib, A., Silk, M., Sacks, G. D., Winograd, R., Hill, C. S., Javed, A. A., Wolfgang, C. L., & Hewitt, D. B. (2024). Abscopal Effect with Liver-Directed Therapy: A Review of the Current Literature and Future Directions. Livers, 4(4), 601-614. https://doi.org/10.3390/livers4040042

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