Immunotherapy in MS-Stable Colorectal Cancer

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1		Oran Zlotnik	--	1937	2023-11-21 02:39:55	\|
2	format	Jason Zhu	Meta information modification	1937	2023-11-22 02:31:09	\|

This entry is adapted from the peer-reviewed paper 10.3390/cancers15215210

Immunotherapy is an innovative treatment that is highly effective against certain cancers, such as skin and lung cancer. However, for colorectal cancer, one of the most prevalent cancers, it does not benefit most patients. Recent research suggests that by treating liver metastases first, immunotherapy might become effective for those with colorectal cancer.

immunotherapy colorectal cancer liver metastases macrophages

1. Enhancing Immunotherapy Efficacy by Targeting Liver Metastases: Lessons from Preclinical Models

1.1. The Role of Myeloid-Derived Suppressor Cells (MDSCs) and Their Effect on CD8 Cells in Animals with Liver Tumors

Yu et al. ^[1] sought to understand the diminished response to immunotherapy observed in the presence of active liver metastases. To this end, they established a dual tumor mouse model, incorporating liver metastases from murine colorectal cancer (MC38 cell line) alongside a corresponding subcutaneous tumor.

In this mouse model, the immunotherapeutic response varied depending on the presence or absence of liver tumors. Mice bearing only MC38 subcutaneous tumors showed a favorable response to immunotherapy. In contrast, those with both MC38 subcutaneous and MC38 liver tumors did not exhibit such a response to immunotherapy. Moreover, when mice had a colorectal subcutaneous tumor (MC38) and melanoma liver tumors (B16F10—murine melanoma), their response to immunotherapy was favorable, mirroring the response in mice without liver tumors. This pattern indicates that the diminished immunotherapeutic response is specifically linked to the presence of similar antigens in both liver and extrahepatic tumors.

Further observations in this model revealed that mice with liver tumors had a systemic reduction in antigen-specific T cells. Building on this, the same research team found that human patients with liver metastases from prostate, breast, and colorectal cancers displayed decreased intratumoral CD8 effector-cell activity. Delving deeper into the mouse model with OT-I cells, it was determined that CD8 cells undergo apoptosis in liver tumors, a process likely triggered by CD11b+ myeloid cells.

Interestingly, this reduced immunotherapeutic response could be reversed. When liver-directed irradiation was applied in the mouse model, there was a notable decrease in CD11b+F4/80+ cells and an increase in T-cell infiltration within the liver. This liver irradiation not only enhanced the efficacy of immunotherapy but also prevented the loss of T cells.

1.2. Tumor-Infiltrating T Regulatory Cells in Mice Models with Liver Tumors

A different research group employed a similar mouse model with synchronous subcutaneous and liver tumors ^[2]. This group similarly found that mice with liver tumors exhibited a diminished response to immunotherapy. However, mice with subcutaneous tumors and synchronous tumors in nonhepatic locations (such as the peritoneum, lungs, or kidneys) responded well to immunotherapy. Notably, these variations in tumor response were absent in immunodeficient mice (SCID), suggesting that the differences are tied to the functionality of the adaptive immune system.

Upon analyzing the T cells infiltrating the subcutaneous tumors, researchers found that CD8 cells in mice with liver tumors showed decreased levels of CTLA-4, PD-1, ICOS, and KI67. Conversely, T regulatory cells (CD4 FOXP3) in these mice displayed increased expression of CTLA-4, ICOS, and PD-L1. Subsequent investigations revealed that the diminished activity of CD8 cells was primarily attributed to a subpopulation of tumor antigen-specific CD8 cells. Depletion of T regulatory cells resulted in the restoration of activity in tumor-specific CD8 cells within subcutaneous tumors.

It was found that the behavior of T regulatory cells impacted the function of MDSCs (myeloid-derived suppressor cells). Earlier work by Yu et al. ^[1] has established that MDSCs were potent suppressors of tumor-specific immunity. This observation is consistent with prior studies highlighting the suppressive role of MDSCs in tumor immunity ^[3]^[4]^[5]^[6].

2. The Potential of Immunotherapy in MS-Stable Colorectal Cancer Patients—Insights from Clinical Trials

Several clinical trials have utilized immune-checkpoint inhibitors to treat patients with MS-stable metastatic colorectal cancer. Specifically, the REGONIVO trial ^[7] utilized a combination of Nivolumab (a PD-1 inhibitor) and Regorafenib (a multikinase inhibitor) in patients with metastatic colorectal and gastric cancer who had not responded to two prior chemotherapy lines. In the colorectal cancer patients group, 50% of the patients without liver metastases (n = 8/16) showed a complete or partial response to the treatment, while only 15% with liver metastases (n = 2/13) had a similar response pattern. Responses were evaluated by the investigators per the Response Evaluation Criteria in Solid Tumors (RECIST). Gastric cancer patients exhibited a similar trend: a 40% response rate with liver metastases and a 67% response rate without liver involvement. The study evaluated the PD-L1 combined positive score (CPS), which is calculated by determining the percentage of tumor cells that are PD-L1 positive. However, this trial did not find a distinct correlation between CPS and treatment outcomes.

Notably, earlier studies that paired immune-checkpoint inhibitors (ICI) with bevacizumab for a similar group of patients did not report significant treatment benefits ^[8]^[9]

While both Regorafenib and Bevacizumab target the VEGF pathway, Regorafenib also interacts with other molecules, such as CSF1R. This molecule is predominantly found on myeloid cells and influences the creation and differentiation of macrophages. Mouse studies ^[1], have shown that inhibiting CSF1R can potentiate immunotherapy for colorectal liver metastases. This might provide insight into why the combination of Regorafenib and ICI yielded better outcomes than the ICI and Bevacizumab pairing.

Several additional recent studies reinforce the idea that colorectal cancer patients could benefit from immunotherapy irrespective of their MSI status ^[10]^[11]^[12]. Notably, the Niche trial ^[10] offers compelling evidence for the potential effectiveness of immunotherapy in MS-stable colorectal tumors without liver metastases. Early-stage primary colorectal tumor patients received immunotherapy before surgical removal of the tumor. Among the 17 MS-stable colorectal cancer patients in the trial, 27% responded to immunotherapy, with post-treatment evaluations revealing 50–100% of their tumor cells as nonviable. Additionally, four patients showed partial responses, with post-treatment viable tumor cells ranging from 60 to 85%. These findings further suggest that immunotherapy could be advantageous for MS-stable colorectal cancer patients, especially those without liver metastases.

3. Combining Immunotherapy with Liver-Targeted Loco-Regional Interventions

3.1. Immunotherapy Combined with Liver Resection

Wang et al. carried out a retrospective analysis examining the effects of immunotherapy on MS-stable colorectal cancer patients, specifically focusing on the presence or absence of liver metastases ^[13]. The study encompassed 95 metastatic microsatellite-stable colorectal cancer patients who did not respond to two prior chemotherapy treatments. These individuals were subsequently treated with immune-checkpoint inhibitors (either anti-PD-1 or anti-PD-L1). Within this cohort, some patients were treated with immunotherapy after their liver metastases were surgically removed, some had ongoing liver metastases during their course of immunotherapy, and a third subset never developed liver metastases.

The most favorable immunotherapy outcomes were observed in patients without any history of liver metastases. These patients exhibited the longest survival rates. Conversely, those with ongoing liver metastases during their immunotherapy treatment showed the least favorable outcomes. Notably, patients who received immunotherapy after surgical removal of their liver metastases demonstrated better response rates than those with ongoing liver metastases.

The disease control rate stood at 58.5% for patients without liver metastases, in stark contrast to a mere 1.9% for those with liver metastases. The median duration of progression-free survival during immunotherapy was 3.0 months for patients postliver resection, compared to 1.5 months for those with active liver metastases. On multivariate analysis, which considered factors like age, gender, primary tumor location, ECOG status, and various mutation statuses, the presence of liver metastases during treatment emerged as the most influential factor affecting progression-free survival during immunotherapy. This association was statistically significant, with a hazard ratio of 7.0 (p < 0.01).

In a related study, Kanikarla et al. ^[14] utilized a dual-agent immunotherapy approach in the preoperative setting to treat 24 patients with colorectal liver metastases, aiming to explore the mechanisms of immunotherapy resistance in colorectal cancer prior to liver-metastases resection.

Liver metastases were analyzed for immune cell infiltration and molecular features. A complete response to immune-checkpoint inhibitors (ICI) was observed only in patients with high microsatellite instability (MSI-HIGH) disease. A lack of response was seen in patients with low microsatellite instability (MS-Stable) disease, which was expected.

However, immune profiling revealed that even patients with microsatellite-stable disease exhibited some immune response to ICI. Post-treatment flow cytometry showed an increase in the expression of LAG3, PD1, ICOS, and TIM3. Additionally, CD-8 cells were more frequent in post-treatment multiplex immunofluorescence, while T regulatory cells and macrophages decreased. This decrease in macrophage activity, as well as increases in CD86 (an antigen-presenting cell-specific marker) and CD69 (a marker of early activation), align with findings in mouse models ^[1]^[15], which suggest that liver-residing macrophages are inducing the apoptosis of tumor-specific CD8 cells. Moreover, a trend towards a lower frequency of CD8+ PD1+ cells was observed in patients with shorter disease-free survival. However, MS-stable disease with preoperative immunotherapy did not exhibit a clinical response. This might be explained by the sequence of treatment. As previously discussed, liver metastases appear to limit the efficacy of immunotherapy. Therefore, resecting the liver metastases before administering checkpoint inhibitors might have resulted in a measurable clinical response to immunotherapy, consistent with the findings from the study by Wang et al. ^[13].

3.2. Immunotherapy Combined with Irradiation and Radioembolization of Liver Metastases

Another modality that may be used to eliminate liver metastases in the context of potentiating immunotherapy is radiation therapy, similar to that previously described in animal models ^[16]^[17]^[18]. Parikh et al. conducted an open-label phase II trial where they combined radiation with ipilimumab and nivolumab to treat patients with metastatic MSS CRC (N = 40) ^[16]. In this trial, patients were first treated with Nivolumab (a PD-1 inhibitor) and Ipilimumab (an anti-CTLA-4 agent). Following the initial dose of immunotherapy, patients received a second dose of both drugs two weeks later and then began radiation therapy (a total of 24 Gy). Tumor samples were analyzed using whole exome sequencing, and blood samples were taken for DNA germline control. All participants were confirmed to have MS-stable tumors, with the majority presenting with metastatic disease. Prior to treatment, only 1 out of 40 patients had stable disease. Post-treatment, 25% of the patients treated per the protocol achieved stable disease, and 10% showed an objective response based on an intention-to-treat analysis. These findings suggest that targeting liver metastases with radiation might enhance the efficacy of immunotherapy.

Monjazeb et al. conducted a multicenter randomized trial where patients with MS-stable colorectal cancer were assigned to one of two radiation protocols combined with immunotherapy ^[17]. The primary goal was to observe a response outside the radiation field. Eighteen patients, who had undergone a median of four previous therapy lines, participated. However, in this trial, the clinical benefits were minimal, with only one patient showing a response outside the irradiated field. However, the study did find treatment-associated changes in the T-cell repertoire within the tumor and blood, and an increased T-cell infiltration in the irradiated area.

In another clinical trial led by Floudas et al. ^[18], a combination of a PD-1 inhibitor (amp224), cyclophosphamide, and stereotactic body radiation was used. Out of the 15 patients in the trial, three experienced stable disease, but no complete or partial responses were recorded. Despite the limited clinical benefits observed, the study found that the polarization of M2 macrophages in the tumor microenvironment was reversed, aligning with findings from animal studies.

Lastly, a phase 2 study involved nine patients with MS-stable colorectal cancer liver metastases ^[19]. They were treated with Y-90 radioembolization, followed by a dual-agent immunotherapy regimen—Tremelimumab and Durvalumab. Unfortunately, all the patients experienced disease progression during or after their first two treatment cycles. The tumor’s lymphocyte infiltration was found to be low, and only transient gene expressions related to radiation treatment were identified.

Overall, it appears that when radiation therapy is combined with immunotherapy, the outcomes vary in treating MS-stable colorectal cancer patients. Some studies suggest potential benefits, while others indicate limited clinical efficacy. These differences might be attributed to the proportion of liver metastases treated in these studies, as well as the sequence of treatment or irradiation protocol. Further research is essential to ascertain the potential of this combination.

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Subjects: Gastroenterology & Hepatology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Oran Zlotnik

Lucyna Krzywon

Jessica Bloom

Jennifer Kalil

Ikhtiyar Altubi

Anthoula Lazaris

Peter Metrakos

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Entry Collection: Gastrointestinal Disease

Update Date: 22 Nov 2023

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