Interleukin-2 PET imaging in patients with metastatic melanoma before and during immune checkpoint inhibitor therapy

Abstract Purpose Immune checkpoint inhibitors can induce a T cell–mediated anti-tumor immune response in patients with melanoma. Visualizing T cell activity using positron emission tomography (PET) might allow early insight into treatment efficacy. Activated tumor–infiltrating T cells express the high-affinity interleukin-2 receptor (IL-2R). Therefore, we performed a pilot study, using fluorine-18-labeled IL-2 ([18F]FB-IL2 PET), to evaluate whether a treatment-induced immune response can be detected. Methods Patients with metastatic melanoma received ~ 200 MBq [18F]FB-IL2 intravenously, followed by a PET/CT scan before and during immune checkpoint inhibitor therapy. [18F]FB-IL2 uptake was measured as standardized uptake value in healthy tissues (SUVmean) and tumor lesions (SUVmax). Response to therapy was assessed using RECIST v1.1. Archival tumor tissues were used for immunohistochemical analyses of T cell infiltration. Results Baseline [18F]FB-IL2 PET scans were performed in 13 patients. SUVmean at baseline was highest in the kidneys (14.2, IQR: 11.6–18.0) and liver (10.6, IQR: 8.6–13.4). In lymphoid tissues, uptake was highest in spleen (10.9, IQR: 8.8–12.4) and bone marrow (2.5, IQR: 2.1–3.0). SUVmax in tumor lesions (n = 41) at baseline was 1.9 (IQR: 1.7–2.3). In 11 patients, serial imaging was performed, three at week 6, seven at week 2, and one at week 4. Median [18F]FB-IL2 tumor uptake decreased from 1.8 (IQR: 1.7–2.1) at baseline to 1.7 (IQR: 1.4–2.1) during treatment (p = 0.043). Changes in [18F]FB-IL2 tumor uptake did not correlate with response. IL-2R expression in four archival tumor tissues was low and did not correlate with baseline [18F]FB-IL2 uptake. No [18F]FB-IL2-related side effects occurred. Conclusion PET imaging of the IL-2R, using [18F]FB-IL2, is safe and feasible. In this small patient group, serial [18F]FB-IL2-PET imaging did not detect a treatment-related immune response. Trial registration Clinicaltrials.gov: NCT02922283; EudraCT: 2014-003387.20

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Case Report: A case of immune checkpoint inhibitor therapy in a patient with multiple sclerosis

F1000Research ◽

10.12688/f1000research.25490.1 ◽

2020 ◽

Vol 9 ◽

pp. 1167

Author(s):

Raju Vaddepally ◽

Soujanya Sodavarapu ◽

Anupama Kutadi ◽

Wesley Taylor ◽

Navneeth Kumar

Keyword(s):

Multiple Sclerosis ◽

Immune Response ◽

Malignant Melanoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Inhibitor Therapy ◽

Response To Treatment ◽

High Dose ◽

Checkpoint Inhibitor Therapy

Immune checkpoint inhibitors (ICIs) have rapidly shifted the landscape of treatments in malignancy with significant improvements in survival paradigm. They have been an attractive armamentarium to the oncologists given the limited immune adverse effects with potential for deeper and durable benefits that haven't been previously noticed with chemotherapy. However, they result in unique toxicities by limiting immune self-tolerance and cause immune-mediated endocrinopathies, such as hypothyroidism, pneumonitis, colitis, hepatitis, myocarditis, meningitis, hypophysitis, etc. As such, they are contraindicated in patients with autoimmune disorders or recipients of organ transplants given the risk for reactivation or flare of the underlying autoimmune disease and rejection of the donor organ in transplants, although sporadic cases have been reported with the use of immunotherapy in such patients. Malignant melanoma is a highly aggressive cancer, with only 15-20% five-year survival rate once it has spread to the lymph nodes or has distant metastasis. ICIs have changed the landscape of advanced melanoma with exponential improvements in survival, the 5-year survival rates are about 50%. Multiple sclerosis (MS) is recognized as T cell-mediated immune response causing inflammation, which causes local inflammatory plaques and demyelination. ICIs are likely to generate an immune response that causes molecular mimicry and cross-react with CNS autoantigens, in turn exacerbating pre-existing immune response and subsequent flare-ups in MS. There is little knowledge about treating such patients with immunotherapy, short of a few case reports and series; in this report, we describe another such case. We present a case of checkpoint inhibitor therapy in a patient with multiple sclerosis who underwent immune checkpoint inhibitor therapy with pembrolizumab for metastatic malignant melanoma who had a complete response to treatment at the cost of MS relapse, which was managed with high-dose steroids.

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Cytokine-Coding Oncolytic Adenovirus TILT-123 Is Safe, Selective, and Effective as a Single Agent and in Combination with Immune Checkpoint Inhibitor Anti-PD-1

Cells ◽

10.3390/cells10020246 ◽

2021 ◽

Vol 10 (2) ◽

pp. 246

Author(s):

Riikka Havunen ◽

Riikka Kalliokoski ◽

Mikko Siurala ◽

Suvi Sorsa ◽

João M. Santos ◽

...

Keyword(s):

T Cell ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Immune Cell ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Interleukin 2 ◽

Oncolytic Adenovirus ◽

Oncolytic Viruses

Oncolytic viruses provide a biologically multi-faceted treatment option for patients who cannot be cured with currently available treatment options. We constructed an oncolytic adenovirus, TILT-123, to support T-cell therapies and immune checkpoint inhibitors in solid tumors. Adenoviruses are immunogenic by nature, are easy to produce in large quantities, and can carry relatively large transgenes. They are the most commonly used gene therapy vectors and are well tolerated in patients. TILT-123 expresses two potent cytokines, tumor necrosis factor alpha and interleukin-2, to stimulate especially the T-cell compartment in the tumor microenvironment. Before entering clinical studies, the safety and biodistribution of TILT-123 was studied in Syrian hamsters and in mice. The results show that TILT-123 is safe in animals as monotherapy and in combination with an immune checkpoint inhibitor anti-PD-1. The virus treatment induces acute changes in circulating immune cell compartments, but the levels return to normal by the middle of the treatment period. The virus is rapidly cleared from healthy tissues, and it does not cause damage to vital organs. The results support the initiation of a phase 1 dose-escalation trial, where melanoma patients receiving a tumor-infiltrating lymphocyte therapy are treated with TILT-123 (NCT04217473).

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Granzyme B PET Imaging of Combined Chemotherapy and Immune Checkpoint Inhibitor Therapy in Colon Cancer

Molecular Imaging and Biology ◽

10.1007/s11307-021-01596-y ◽

2021 ◽

Author(s):

Julian L Goggi ◽

Siddesh V Hartimath ◽

Tan Yun Xuan ◽

Shivashankar Khanapur ◽

Beverly Jieu ◽

...

Keyword(s):

Colon Cancer ◽

Combination Therapy ◽

Pet Imaging ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Immune Cell ◽

Checkpoint Inhibitor ◽

Granzyme B ◽

Cell Populations ◽

Tumor Uptake

Abstract Purpose Chemotherapeutic adjuvants, such as oxaliplatin (OXA) and 5-fluorouracil (5-FU), that enhance the immune system, are being assessed as strategies to improve durable response rates when used in combination with immune checkpoint inhibitor (ICI) monotherapy in cancer patients. In this study, we explored granzyme B (GZB), released by tumor-associated immune cells, as a PET imaging-based stratification marker for successful combination therapy using a fluorine-18 (18F)-labelled GZB peptide ([18F]AlF-mNOTA-GZP). Methods Using the immunocompetent CT26 syngeneic mouse model of colon cancer, we assessed the potential for [18F]AlF-mNOTA-GZP to stratify OXA/5-FU and ICI combination therapy response via GZB PET. In vivo tumor uptake of [18F]AlF-mNOTA-GZP in different treatment arms was quantified by PET, and linked to differences in tumor-associated immune cell populations defined by using multicolour flow cytometry. Results [18F]AlF-mNOTA-GZP tumor uptake was able to clearly differentiate treatment responders from non-responders when stratified based on changes in tumor volume. Furthermore, [18F]AlF-mNOTA-GZP showed positive associations with changes in tumor-associated lymphocytes expressing GZB, namely GZB+ CD8+ T cells and GZB+ NK+ cells. Conclusions [18F]AlF-mNOTA-GZP tumor uptake, driven by changes in immune cell populations expressing GZB, is able to stratify tumor response to chemotherapeutics combined with ICIs. Our results show that, while the immunomodulatory mode of action of the chemotherapies may be different, the ultimate mechanism of tumor lysis through release of Granzyme B is an accurate biomarker for treatment response.

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