Intralesional Interleukin-2 Research Articles

Intralesional interleukin 6 is associated with intraplaque hemorrhage in carotid atherosclerotic plaques

Intralesional interleukin 6 is associated with intraplaque hemorrhage in carotid atherosclerotic plaques

Variable Outcome of Immunotherapy in Advanced Multiple Cutaneous Squamous Cell Carcinomas in Two Patients with Recessive Dystrophic Epidermolysis Bullosa

Cutaneous squamous cell carcinoma (cSCC) is a major complication of recessive dystrophic epidermolysis bullosa (RDEB) that has high morbidity and mortality rates and unmet therapeutic needs. The aim of this study was to evaluate the molecular pattern of cSCC and the clinical course of immunotherapy in 2 RDEB patients with multiple advanced cSCC. Clinical course and disease staging were evaluated retrospectively. The tumour tissues were subjected to immunohistochemical staining. DNA from the blood and cSCC samples was subjected to massive parallel sequencing, and somatic mutations were determined. Patient 1 survived for over 2 years as disease control was achieved with cemiplimab and intralesional interleukin-2. The target advanced cSCC demonstrated a high rate of somatic mutations and strong expression of the immune markers, indoleamine 2,3-dioxygenase, programmed cell death protein ligand 1, and lymphocyte-activation gene 3. The patient ultimately succumbed to complications of oesophageal carcinoma. Patient 2 had an undifferentiated cSCC on the foot, which displayed a low mutational burden and did not express immune markers. The tumour progressed quickly even with cemiplimab therapy. These 2 cases underscore the challenges of cSCC treatment for RDEB. Multiple tumours with different molecular and immune profiles occur concomitantly or sequentially, and surgical excision is not always possible because of the anatomical and tissue constraints imposed by the disease itself. In conclusion, programmed cell death protein 1 inhibitors are approved and effective in treating metastatic and locally advanced cSCC. Our experience and the literature suggest that cemiplimab is an option in patients with RDEB if surgery is not. Somatic mutations and the immune microenvironment should be characterized to predict therapeutic response, particularly in aggressive undifferentiated tumours.

Abstract 5353: Graph representation learning of tumor topology from spatial imaging data

Abstract Recently, novel technologies have enabled spatially resolved multiplexed protein profiling of tumors; however, there is an unmet need for unbiased detection of spatial structures within the tissue. By encoding multiplexed images as a graph, we produce an efficient and well-studied graph representation that allows for the application of sophisticated machine learning methods, particularly graph neural networks (GNNs) and graph autoencoders (GAE). While GNNs have recently become popular tools in the analysis of spatial data, current GNN methods are limited by production of cell-level representations rather than graph-level representations. To understand patterns of local tissue structure and protein expression, we implemented a generalizable GAE framework that summarizes marker intensity and morphological values with the local topology of neighboring cells. In this way, each local cellular graph is represented as a single point in the lower dimensional space. We show that our framework generates low-dimensional features that reflect both cellular attributes and tissue structure. We demonstrate that clustering local structure in 318 fields of view from 22 tumor lesions across 7 patients with in-transit melanoma captured using multiplexed immunofluorescence (mpIF) can produce spatial motifs predictive of response to intralesional interleukin-2 (IL-2) immunotherapy. Additionally, we applied our framework to mpIF data of 146 high grade serous ovarian cancer tumors across 50 patients. We identify clusters with higher CD8+ T cell infiltration that associate with homologous recombination deficiency. Our method can be readily applied to various spatially resolved multiplexed imaging platforms, and the resulting embeddings provide a compressed representation of subgraphs that can be used in further classification or regression analysis of patient- and/or image-level histological, clinical, or genomic labels. Citation Format: Nicholas Ceglia, Samuel S. Freeman, Maryam Pourmaleki, Andrew McPherson, Sohrab P. Shah. Graph representation learning of tumor topology from spatial imaging data. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5353.

Additive Intralesional Interleukin-2 Improves Progression-Free Survival in a Distinct Subgroup of Melanoma Patients with Prior Progression under Immunotherapy.

Simple SummaryDespite the immense progress in systemic treatment of advanced unresectable melanoma with immunotherapies, there is still an unmet need for patients showing primary resistance. We show that addition of intratumoral injections of the immune modulator Interleukin-2 can overcome primary resistance in a distinct subset of patients and this effect is associated with an intratumoral increase of certain inflammatory cells supporting the paradigm of turning a “cold” into a “hot” tumor.A considerable amount of melanoma patients show primary resistance to PD-1 and CTLA-4 inhibitors. We have previously reported a beneficial role of intralesional Interleukin-2 (IL-2) in 9 melanoma patients developing new locoregional metastases under immunotherapy. We have now expanded this retrospective cohort to 27 patients. Patients were evaluated for their tumor characteristics, treatment response and progression-free and overall survival (PFS/OS). In 16 patients, tumor biopsies before and under IL-2 treatment were evaluated for immune markers. The median follow-up time was 16 (1–59) months from start of IL-2 treatment. Treatment response of locoregional metastases was seen in 74% of all patients and response of distant organ metastases in 37% of stage IV patients, respectively. A prolonged PFS and OS was significantly associated with absence of active distant metastases (p = 0.008), response of locoregional metastases (p = 0.002), increase of absolute eosinophil count (AEC) (p < 0.001) and an influx of CD8+ tumor infiltrating lymphocytes (TILs) (p = 0.003). Additional intralesional treatment with IL-2 in patients with locoregional progression under immunotherapy is a well-tolerated, easily feasible therapeutic option especially in patients lacking active distant metastases. A careful patient selection can lead to an improved PFS and OS.

Durability of Complete Response to Intralesional Interleukin-2 for In-Transit Melanoma.

BackgroundIntralesional injection of interleukin-2 (IL-2) for in-transit melanoma (ITM) is associated with a high rate of complete response. However, there is a paucity of data on treatment durability and long-term outcomes.ObjectivesTo provide long-term data on patients with a complete response to IL-2 therapy for ITM.MethodsConsecutive patients with ITM, treated with intralesional IL-2 therapy, at the Tom Baker Cancer Center were identified from April 2009 to August 2019. All patients received at least 4 cycles (every 2 weeks) of IL-2 (5 MIU/mL). Complete response was defined as sustained (ie, 3 months) clinical complete remission of all known in-transit disease.ResultsSixty-five patients were treated with curative intent for in-transit disease with intralesional IL-2. Complete clinical response was identified in 44.6% (29/65). In this subset of patients, the median number of lesions per patient was 9 (range 1-40). The median total dose of IL-2 was 0.8 mL (IQR 0.4-1.5) per lesion. One patient received isolated limb infusion and 13.8% (4/29) received systemic immunotherapy as part of their initial management. At a median follow-up of 27 months (IQR 16-59), 34.5% (10/29) developed recurrent disease. Of these patients, 50.0% (5/10) presented with synchronous in-transit and distant metastases. The median time to recurrence was 10.5 months (IQR 5.8-16.3).ConclusionWith long-term follow-up, 65.5% of complete responders have a durable response to intralesional IL-2 therapy. In this cohort of patients, local in-transit recurrence is most likely to occur within 12 months and is often associated with concomitant distant disease.

Evaluation of Intra-Lesional Interleukin 2 for the Treatment of In-Transit Melanoma Disease: L'évaluation de l'interleukine-2 intralésionnelle pour traiter les mélanomes en transit.

Intra-lesional interleukin 2 (IL-2) therapy trials for the treatment of in-transit melanoma using different treatment protocols have been published reporting varied results. This study assesses the results of IL-2 therapy in our institution and to evaluate the reproducibility of our response rates when using the same treatment protocol as another Canadian centre. A retrospective review was undertaken of patients with in-transit melanoma who were treated with intralesional IL-2 in a single institution from 2010 to 2016. Responses were evaluated using RECIST criteria. Demographic data, tumour characteristics, follow-up data, in-transit-free interval, and survival data were collected and analysed. Forty-nine patients were identified. Overall tumour response rate was 72%, including complete response in 23 patients (47%) and partial response in 12 patients (24%). Stable disease was observed in 4% of patients and progressive disease in 25%. The main side effects were minor discomfort with injections and auto-limited flu-like symptoms. The presence of tumour-infiltrating lymphocytes may be a predictor of better response. This study confirms prior experience with intra-lesional IL-2, demonstrating it to be an effective, safe, and well-tolerated therapy for in-transit melanoma. Tumour-infiltrating lymphocytes as a predictor of better response warrant further study.

Locoregional management of in-transit metastasis in melanoma: an Ontario Health (Cancer Care Ontario) clinical practice guideline.

The purpose of this guideline is to provide guidance on appropriate management of satellite and in-transit metastasis (itm) from melanoma. The guideline was developed by the Program in Evidence-Based Care (pebc) of Ontario Health (Cancer Care Ontario) and the Melanoma Disease Site Group. Recommendations were drafted by a Working Group based on a systematic review of publications in the medline and embase databases. The document underwent patient- and caregiver-specific consultation and was circulated to the Melanoma Disease Site Group and the pebc Report Approval Panel for internal review; the revised document underwent external review. "Minimal itm" is defined as lesions in a location with limited spread (generally 1-4 lesions); the lesions are generally superficial, often clustered together, and surgically resectable. "Moderate itm" is defined as more than 5 lesions covering a wider area, or the rapid development (within weeks) of new in-transit lesions. "Maximal itm" is defined as large-volume disease with multiple (>15-20) 2-3 cm nodules or subcutaneous or deeper lesions over a wide area.■ In patients presenting with minimal itm, complete surgical excision with negative pathologic margins is recommended. In addition to complete surgical resection, adjuvant treatment may be considered.■ In patients presenting with moderate unresectable itm, consider using this approach for localized treatment: intralesional interleukin 2 or talimogene laherparepvec as 1st choice, topical diphenylcyclopropenone as 2nd choice, or radiation therapy as 3rd choice. Evidence is insufficient to recommend intralesional bacille Calmette- Guérin or CO2 laser ablation outside of a research setting.■ In patients presenting with maximal itm confined to an extremity, isolated limb perfusion, isolated limb infusion, or systemic therapy may be considered. In extremely select cases, amputation could be considered as a final option in patients without systemic disease after discussion at a multidisciplinary case conference.■ In cases in which local, regional, or surgical treatments for itm might be ineffective or unable to be performed, or if a patient has systemic metastases at the same time, systemic therapy may be considered.

Checkpoint inhibitor treatment in patients with isolated in-transit melanoma metastases.

10070 Background: In the context of multiple in-transit melanoma metastases without nodal involvement, a variety of treatment modalities have historically been employed including surgery, laser, isolated limb perfusion/infusion, intralesional interleukin-2, T-VEC and electrochemotherapy. Unfortunately, most patients treated with these modalities experience subsequent disease progression. While checkpoint inhibitors (CPI) are a standard of care for bulky unresectable stage III and for stage IV melanoma, patients with isolated in-transit metastases were rarely included in registration studies. There are anecdotal reports of lower response rates in these patients despite them having disease characteristics that would usually be associated with a good response. Methods: We report data from 11 retrospective patient cohorts treated at cancer centres across Europe who received CPI between 2016 and April 2019. All patients had multiple in-transit metastases without clinical or radiological evidence of nodal or distant disease. Disease response was assessed using CT, PET-CT or MRI depending on clinical indication. All patients had at least one prior resection of loco-regional relapsed disease and were deemed not curable by further surgery. Results: Sixty three patients meeting criteria were identified, 40 females and 23 males. Median age was 72 years and 54 (86%) patients had a normal lactate dehydrogenase (LDH). 19 (30%) patients had a BRAF mutation. At treatment initiation, the majority 55 (87.3%) received single agent PD-1 inhibitor, 7 (11.1%) combination ipilimumab + nivolumab and 1 (1.6%) received single agent anti-CTLA 4. The overall response rate was 62% for the full population. The response rate with anti-PD1 monotherapy was 59%. With a median FU of 23 months, the median PFS was 26 months, median OS not reached. OS estimates with 95% CI: 12 month - 93% (87-100%), 24 month - 88% (80-98%), 36 month - 80% (67-95%). Conclusions: The results show a high response rate to CPI in patients with in-transit metastases and support early treatment with CPI following identification of in-transit metastases not curable with surgery whilst disease characteristics remain favourable.

Primary cutaneous CD4+ small/medium pleomorphic T-cell lymphoproliferative disorder in a woman successfully treated with intralesional interleukin injection and occlusive corticosteroid

Primary cutaneous CD4⁺ small/medium pleomorphic T-cell lymphoproliferative disorder in a woman successfully treated with intralesional interleukin injection and occlusive corticosteroid

Successful combination therapy of systemic checkpoint inhibitors and intralesional interleukin-2 in patients with metastatic melanoma with primary therapeutic resistance to checkpoint inhibitors alone.

Systemic immunotherapy with PD-1 inhibitors is established in the treatment of metastatic melanoma. However, up to 60% of patients do not show long-term benefit from a PD-1 inhibitor monotherapy. Intralesional treatments with immunomodulatory agents such as the oncolytic herpes virus Talimogene Laherparepvec and interleukin-2 (IL-2) have been successfully used in patients with injectable metastases. Combination therapy of systemic and local immunotherapies is a promising treatment option in melanoma patients. We describe a case series of nine patients with metastatic melanoma and injectable lesions who developed progressive disease under a PD-1 inhibitor monotherapy. At the time of progressive disease, patients received intratumoral IL-2 treatment in addition to PD-1 inhibitor therapy. Three patients showed complete, three patients partial response and three patients progressive disease upon this combination therapy. IHC stainings were performed from metastases available at baseline (start of PD-1 inhibitor) and under combination therapy with IL-2. IHC results revealed a significant increase of CD4+ and CD8+ T cells and a higher PD-1 expression in the inflammatory infiltrate of the tumor microenvironment in metastases from patients with subsequent treatment response. All responding patients further showed a profound increase of the absolute eosinophil count (AEC) in the blood. Our case series supports the concept that patients with initial resistance to PD-1 inhibitor therapy and injectable lesions can profit from an additional intralesional IL-2 therapy which was well tolerated. Response to this therapy is accompanied by increase in AEC and a strong T cell-based inflammatory infiltrate.

1255P - Impact of intralesional interleukin 2 (IL2) for in-transit melanoma in two Canadian centres

Background: In-transit (IT) melanoma is a form of metastatic disease that is associated with high morbidity and is often refractory to treatment. Intralesional (IAL) IL2 has been increasingly utilized to obtain loco-regional control. This study utilizes a national registry to evaluate response and duration of response of standardized IAL therapy at tertiary centres in 2 provinces. Methods: Patients (pts) receiving IAL IL2 between 2000 and 2017 were included. Data regarding patient demographics, stage, extent of disease, and all treatments were collected. All pts received a median IL2 dose of 12 million IU given as an IAL injection every 2 to 4 weeks repeated 2 to 8 times to complete a session. Results: A total of 87 pts aged 21 to 94 (mean: 69 yrs) were included. IT disease was located in the following areas: limbs in 68 pts (79%), head and neck in 13 pts (15%) and trunk in 5 pts (6%). 20% of pts developed IT within 3 months of primary diagnosis, 69% developed IT after 6 months and 11% after 3 years. IT lesions per individual ranged from 1 to 40+; 45% had >10 lesions. Patients had a complete response rate of 32% (28 pts) and a partial response rate of 38% (33 pts). 27 (31%) pts experienced a recurrence after their 1st IL2 session, with a mean of 225 days (median: 204). Of these pts, 15 (56%) pts developed loco-regional recurrences, while 6 (22%) developed distant metastases and 6 (22%) had both distant and loco-regional recurrences. 27 pts (31%) received systemic treatment for metastatic disease. 18 (21%) pts died of disease, while 3% died of other causes while disease was present. 7 (8%) died of other causes with disease status unknown, and 25 (29%) and 34 (39%) are recorded alive with more than a year (1 to 11 yrs) or less than a year follow up, respectively. No grade 3 or 4 toxicity was experienced by pts who received IL2 therapy. On multi-variant analysis, age, extent of disease and prior systemic therapy did not impact overall response (X2 test, p > 0.05). Conclusions: IAL IL2 appears to be an effective therapeutic option for pts with advanced melanoma and IT disease, with an overall response rate of 70%. With further long-term follow up of these pts, the impact on overall survival can be determined. Legal entity responsible for the study: Global Melanoma Research Network. Funding: Global Melanoma Research Network. Disclosure: All authors have declared no conflicts of interest.

A durable response following intralesional interleukin-2 in treatment-refractory melanoma

A durable response following intralesional interleukin-2 in treatment-refractory melanoma

100% Complete response rate in patients with cutaneous metastatic melanoma treated with intralesional interleukin (IL)-2, imiquimod, and topical retinoid combination therapy: Results of a case series

Patients with cutaneous melanoma metastases have experienced excellent responses to intralesional interleukin (IL)-2. This has led to its recent inclusion into the US National Comprehensive Cancer Network guidelines for management of cutaneous melanoma metastases. Despite this, intralesional IL-2 has not been highlighted in the US literature nor have US physicians adopted it. We sought to evaluate the effectiveness of intralesional IL-2 combined with topical imiquimod and retinoid for treatment of cutaneous metastatic melanoma. A retrospective case series of 11 patients with cutaneous metastatic melanoma were treated with intralesional IL-2 combined with topical imiquimod and retinoid. A 100% complete local response rate with long-term follow-up (average of 24months) was seen in all 11 patients treated with this proposed regimen. Biopsy specimens of treated sites confirmed absence of malignant cells. The most common treatment-related adverse event was rigors. Small number of patients, retrospective review of charts, and lack of a comparison group were limitations. Intralesional IL-2 administered concomitantly with topical imiquimod and a retinoid cream is a promising therapeutic option for managing cutaneous melanoma metastases. The regimen was well tolerated and should be considered as a reasonable alternative to surgical excision.

High response rate of in-transit melanoma metastases to intralesional interleukin 2

High response rate of in-transit melanoma metastases to intralesional interleukin 2

Pathologic complete response to intralesional interleukin-2 therapy associated with improved survival in melanoma patients with in-transit disease.

Melanoma patients with in-transit disease have a high mortality rate despite various treatment strategies. The aim of this study was to validate the role of intralesional interleukin (IL)-2, to understand its mechanism of action, and to better understand factors that may influence its response. We retrospectively collected the clinicopathological data of 31 consecutive patients who presented to a tertiary care cancer center for treatment of in-transit melanoma with intralesional IL-2. Kaplan-Meier survival curves and multivariable Cox regression analysis were performed. Immunohistochemistry (IHC) was used to better understand the immune response to localized IL-2 therapy. Targeted next-generation sequencing was performed to genomically characterize the tumors. Ten patients (10/31, 32 %) achieved a pathologic complete response (pCR), 17/21 (55 %) had a partial response, and 4/21 (19 %) had progressive disease on treatment. pCR to IL-2 therapy was associated with overall survival (log-rank p = 0.004) and improved progression-free survival (PFS) [adjusted hazard ratio (HR) 0.11; 95 % CI 0.02-0.47; p = 0.003). A higher CD8+ T cell infiltrate was identified in in-transit lesions with a pCR compared with the other lesions (mean IHC score 3.78 vs. 2.61; p = 0.01). Patients with an elevated CD8+ infiltrate demonstrated an improved PFS (unadjusted HR 0.08; 95 % CI 0.01-0.52; p = 0.008). Thirty-two percent of patients achieved pCR with intralesional IL-2 therapy and had a significantly improved PFS compared with the rest of the cohort, which may be explained by a systemic CD8+ T-cell response.

Treatment of in-transit melanoma with intra-lesional interleukin-2: a systematic review.

Several phase II studies have assessed intra-lesional interleukin-2 (IL-2) for the treatment of in-transit melanoma. This systematic review addresses the efficacy and side effect profile of IL-2. MEDLINE, EMBASE, Cochrane Library, and Google Scholar databases were searched from 1980 to 2012 for studies evaluating the clinical response to IL-2 for in-transit melanoma. Titles and abstracts were screened by two independent researchers for suitability using predetermined inclusion and exclusion criteria. A modified quality assessment tool for observational studies was used. Data were pooled and analyzed to determine lesion and patient response rates. Forty-nine studies were identified. Forty-three did not meet inclusion criteria, leaving six observational trials. Heterogeneity was seen in IL-2 dosage and treatment interval. Response rate was variable as well. Overall, 2,182 lesions and 140 patients were treated in these six studies. Pooling the lesions, complete response was seen in 78%. Pooling subjects, 50% achieved a complete response. Treatment was generally well tolerated, with localized pain and swelling, and mild flu-like symptoms. There were only three grade 3 adverse events reported, including rigors, headache, and fever with arthralgia. Intra-lesional IL-2 safely and effectively provides locoregional control of in-transit melanoma.

Intra‐lesional interleukin‐2 therapy for in transit melanoma

Intra-lesional interleukin-2 (IL-2) is effective in treating in transit melanoma metastases. Results from multiple studies were examined to evaluate the efficacy of IL-2 for in transit disease. In the published literature, complete response ranged from 0% to 69% per patient, and 41% to 96% per lesion, with excellent tolerability. Combining the results of six studies show complete response in 50% of patients and 78% of lesions. Intra-lesional IL-2 should be considered early in the course of treatment for in transit disease, ahead of other, more toxic therapies.

Microinvasive Melanoma

Surgical excision is the treatment of choice for primary melanomas and radiation therapy is the accepted alternative for the subset of lesions not amenable to surgery. With the recent rise in melanoma incidence, especially in the elderly, there are a growing number of cases that are neither amenable to surgery nor radiation therapy. In this article, we review pharmacotherapeutic approaches to microinvasive melanoma (invasive radial growth phase melanoma) that might be considered in such circumstances. There are no approved drugs for the treatment of primary melanoma and randomized controlled trials with 5 or more years of follow-up have not been performed. The limited studies and numerous case series in the literature on pharmacologic treatment of primary melanoma have focused on topical therapies. Accordingly, we provide a review of the potential pharmacotherapeutic agents in the treatment of microinvasive melanoma by extrapolating from the available limited literature on the use of fluorouracil, azelaic acid, retinoic acid derivatives, interferon (IFN)-α, imiquimod, and other agents for melanoma in situ, invasive melanoma, and epidermotropic melanoma metastases. Our review indicates that topical fluorouracil and tretinoin are not effective as single agents. The efficacy of azelaic acid, tazarotene, cidofovir, and intralesional IFN-α, interleukin-2, and IFN-β is undefined. Imiquimod is the most studied and promising agent; however, optimal dosage, therapeutic regimen, and survival rates are unknown. In the face of a growing demand for non-surgical treatments, formal clinical trials are needed to ascertain the role of pharmacotherapeutic agents in the treatment of microinvasive melanoma.

Complete regression of subcutaneous and cutaneous metastatic melanoma with high-dose intralesional interleukin 2 in combination with topical imiquimod and retinoid cream

Complete regression of subcutaneous and cutaneous metastatic melanoma with high-dose intralesional interleukin 2 in combination with topical imiquimod and retinoid cream

Targeting Melanoma Sites in Vivo can Induce Complete Tumor Ablation and Prolong Patient Survival: An Exploratory Study

Dermal and subdermal metastases as well as primary invasive melanoma allow an excellent opportunity to study the effects of intralesional therapy. The therapy consisted of weekly intralesional administration of nontoxic doses of granulocyte-macrophage colony stimulating factor at 500 microgram, and in case of failure to establish complete tumor response at the injection sites in 4-6 weeks; weekly intralesional interleukin-2 at 18 million international units was substituted. The results revealed complete response in patients with multiple small in transit metastases ranging in size from few millimeters to one centimeter (n=4) for over 31-48 months, but not in any of the large sclerotic lesions of 2 centimeter or more (n=3). Complete responses were elicited for 6 months in one of two patients with distant metastases who had palpable subdermal tumors treated with granulacyte-macrophage colony stimulating factor. A patient with primary cutaneous melanoma with a satellite lesion and and a large regional lymph node metastasis received both cytokines in the skin sites, one week prior to surgery, had complete tumor necrosis, intense immune response at the injection sites and at the regional lymph nodes, with over 36 months disease free survival. This could be an affective new approach to tumor-specific adjuvant immunotherapy.