Interleukin-2 (IL-2) is a component of most protocols of adoptive cell transfer (ACT) therapy for cancer, but is limited by short exposure and high toxicities. NKTR-214 is a kinetically-engineered ...IL-2 receptor βγ (IL-2Rβγ)-biased agonist consisting of IL-2 conjugated to multiple releasable polyethylene glycol chains resulting in sustained signaling through IL-2Rβγ. We report that ACT supported by NKTR-214 increases the proliferation, homing and persistence of anti-tumor T cells compared to ACT with IL-2, resulting in superior antitumor activity in a B16-F10 murine melanoma model. The use of NKTR-214 increases the number of polyfunctional T cells in murine spleens and tumors compared to IL-2, and enhances the polyfunctionality of T and NK cells in the peripheral blood of patients receiving NKTR-214 in a phase 1 trial. In conclusion, NKTR-214 may have the potential to improve the antitumor activity of ACT in humans through increased in vivo expansion and polyfunctionality of the adoptively transferred T cells.
Abstract
Background
Diarrhea and colitis are the second most common immune checkpoint inhibitor (ICPI)-induced adverse events. However, a comprehensive characterization of the endoscopic and ...histologic features of ICPI-induced diarrhea and colitis is lacking. Therefore, we aimed to describe endoscopic and histologic features of ICPI-induced gastrointestinal toxicities and to assess their association with patients' clinical characteristics and outcomes.
Methods
We retrospectively reviewed records of 53 patients with ICPI-related diarrhea/colitis between 2011 and 2017. We collected data on demographics, diarrhea/colitis grade, treatment, and endoscopic and histologic findings. Long-term follow-up included repeat endoscopy findings, diarrhea recurrence, and overall survival. We compared groups by treatment, endoscopic and histologic findings, and constructed Kaplan-Meier survival curves.
Results
Most patients had grade 2 or higher diarrhea (87%) and colitis (60%). Thirty-one patients were successfully treated with corticosteroids, and 22 additionally required infliximab. On endoscopy, 21 (40%) patients had ulcerations and 22 (42%) had nonulcerative inflammation. Patients with ulcerations had more steroid-refractory disease (P = 0.044) and high-grade diarrhea (P = 0.033). Histology showed mostly acute (23%) or chronic (60%) inflammation. During mean follow-up duration of 18.9 months, 19 (36%) developed recurrent diarrhea. Most patients had persistent endoscopic (8/13, 62%) and histologic (9/11, 82%) inflammation. Patients with higher-grade adverse events had improved survival. Higher-grade colitis was associated with endoscopic inflammation (P = 0.039), but grade of diarrhea was not associated with endoscopic inflammation or grade of colitis.
Conclusion
10.1093/ibd/izy104_video1
izy104.video1
5808053084001
Little prospective data are available on clinical outcomes and immune correlates from combination radiation and immunotherapy. We conducted a phase I trial (NCT02239900) testing stereotactic ablative ...radiotherapy (SABR) with ipilimumab.
SABR was given either concurrently (1 day after the first dose) or sequentially (1 week after the second dose) with ipilimumab (3 mg/kg every 3 weeks for 4 doses) to five treatment groups: concurrent 50 Gy (in 4 fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and sequential 60 Gy (in 10 fractions) to lung or liver. MTD was determined with a 3 + 3 dose de-escalation design. Immune marker expression was assessed by flow cytometry.
Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the radiation field was assessable in 31 patients. Three patients (10%) exhibited partial response and 7 (23%) experienced clinical benefit (defined as partial response or stable disease lasting ≥6 months). Clinical benefit was associated with increases in peripheral CD8
T cells, CD8
/CD4
T-cell ratio, and proportion of CD8
T cells expressing 4-1BB and PD1. Liver (vs. lung) irradiation produced greater T-cell activation, reflected as increases in the proportions of peripheral T cells expressing ICOS, GITR, and 4-1BB.
Combining SABR and ipilimumab was safe with signs of efficacy, peripheral T-cell markers may predict clinical benefit, and systemic immune activation was greater after liver irradiation.
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Purpose of Review
The use of cytokines in harnessing the immune system to eradicate cancer has been an important treatment modality. However, the dose-limiting toxicities of these cytokines limited ...their usage in clinic. Here, we review the basic biology of cytokines involved in the treatment of melanoma and discuss their therapeutic applications. Moreover, we describe several innovative technological approaches that have been developed to improve the pharmacokinetics, safety, and efficacy of these cytokines.
Recent Findings
The safety and the anti-tumor activity of newly engineered cytokines including PEGylated IL-2 (NKTR-214), PEGylated IL-10 (AM0010), and IL-15 super agonist (ALT-803) have been evaluated in clinical trials with encouraging clinical activity and acceptable safety profile, both as single agents and in combination with immuno-oncology agents.
Summary
A greater understanding of the mechanisms of action and effective dosing of these newly engineered cytokine together with determination of optimum combination therapy regimens may yield greater clinical benefits in the future.
High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use ...in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rβ). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in mice. NKTR-214 shows superior anti-tumor activity over native IL-2 and systemically expands anti-tumor CD8
T cells while inducing Treg depletion in tumor tissue but not in the periphery. Similar trends of intratumoral Treg dynamics are observed in a small cohort of patients treated with NKTR-214. Mechanistically, intratumoral Treg depletion is mediated by CD8
Teff-associated cytokines IFN-γ and TNF-α. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies.
Background
Gastrointestinal (GI) immune-related adverse events (irAEs) commonly limit immune checkpoint inhibitors’ (ICIs) treatment, which is very effective for metastatic melanoma. The independent ...impact of GI-irAEs on patients’ survival is not well studied. We aimed to assess the impact of GI-irAEs on survival rates of patients with metastatic melanoma using multivariate model.
Methods
This is a retrospective study of patients with metastatic melanoma who developed GI-irAEs from 1/2010 through 4/2018. A number of randomized patients who did not have GI-irAEs were included as controls. Kaplan–Meier curves and log-rank test were used to estimate unadjusted survival durations. The Cox proportional hazards model was used to evaluate survival predictors; irAEs were included as time-dependent variables.
Results
A total of 346 patients were included, 173 patients had GI-irAEs; 124 (72%) received immunosuppression. In multivariate Cox regression, ECOG 2–3 (HR 2.57, 95%CI 1.44–4.57;
P
< 0.01), LDH ≥ 618 IU/L (HR 2.20, 95% CI 1.47–3.29;
P
< 0.01), stage M1c (HR 2.21, 95% CI 1.35–3.60;
P
< 0.01) were associated with worse OS rates. Any grade GI-irAEs (HR 0.53, 95% CI 0.36–0.78;
P
< 0.01) was associated with improved OS rates. Immunosuppressive treatment did not affect OS (
P
= 0.15). High-grade diarrhea was associated with improved OS (
P
= 0.04). Patients who developed GI-irAEs had longer PFS durations on Cox model (HR 0.56, 95% CI 0.41–0.76;
P
< 0.01).
Conclusion
GI-irAEs are associated with improved OS and PFS in patients with metastatic melanoma. Furthermore, higher grades of diarrhea are associated with even better patients’ OS rates.
Checkpoint inhibitors (CPIs) have revolutionized the treatment of cancer, but their use remains limited by off-target inflammatory and immune-related adverse events. Solid organ transplantation (SOT) ...recipients have been excluded from clinical trials owing to concerns about alloimmunity, organ rejection, and immunosuppressive therapy. Thus, we conducted a retrospective study and literature review to evaluate the safety of CPIs in patients with cancer and prior SOT.
Data were collected from the medical records of patients with cancer and prior SOT who received CPIs at The University of Texas MD Anderson Cancer Center from January 1, 2004, through March 31, 2018. Additionally, we systematically reviewed five databases through April 2018 to identify studies reporting CPIs to treat cancer in SOT recipients. We evaluated the safety of CPIs in terms of alloimmunity, immune-related adverse events, and mortality. We also evaluated tumor response to CPIs.
Thirty-nine patients with allograft transplantation were identified. The median age was 63 years (range 14-79 years), 74% were male, 62% had metastatic melanoma, 77% received anti-PD-1 agents, and 59% had prior renal transplantation, 28% hepatic transplantation, and 13% cardiac transplantation. Median time to CPI initiation after SOT was 9 years (range 0.92-32 years). Allograft rejection occurred in 41% of patients (11/23 renal, 4/11 hepatic, and 1/5 cardiac transplantations), at similar rates for anti-CTLA-4 and anti-PD-1 therapy. The median time to rejection was 21 days (95% confidence interval 19.3-22.8 days). There were no associations between time since SOT and frequency, timing, or type of rejection. Overall, 31% of patients permanently discontinued CPIs because of allograft rejection. Graft loss occurred in 81%, and death was reported in 46%. Of the 12 patients with transplantation biopsies, nine (75%) had acute rejection, and five of these rejections were T cell-mediated. In melanoma patients, 36% responded to CPIs.
SOT recipients had a high allograft rejection rate that was observed shortly after CPI initiation, with high mortality rates. Further studies are needed to optimize the anticancer treatment approach in these patients.
Immunomodulatory drugs that leverages host immune mechanisms to destroy tumor cells have been met with great promise in the treatment of cancer. Immunotherapy, targeting cytotoxic ...T‐lymphocyte‐associated antigen 4 (CTLA‐4) and the programmed cell death 1 (PD‐1) receptor and its ligand (PD‐L1) have shown tremendous improvements in the survival of patients with advanced solid tumors. However, the development of dermatologic toxicity (DT) is a consequence to immunotherapy. Review of published reports of the DT to immunotherapy revealed patients receiving anti‐CTCLA‐4 antibody or anti‐PD‐1/PD‐L1 antibody often develop a DT of any type and grade. In this article, of the 3825 patients who were treated with anti‐PD‐1 and of 556 patients receiving anti‐PD‐L1, DT of any type and grade were reported in 1474 (∼39%) and 95 (∼17%) of patients, respectively. The emergence of specific types of DT to immunotherapy is beginning to be recognized can be categorized into four groups: (a) inflammatory, (b) immunobullous, (c) alteration of keratinocytes and (d) alteration of melanocytes. Lichenoid dermatitis and bullous pemphigoid appear to be DT more associated with anti‐PD‐1/PD‐L1 antibody. The DT profile in patients receiving immunotherapy is diverse, and early recognition of specific types of DT that clinicians may encounter is critical for optimal patient care
Immune checkpoint inhibitors (ICPIs) are gaining increasing popularity as an efficacious treatment for advanced malignancies. ICPI treatment can be complicated by diarrhea and colitis. Systemic ...steroids are the first line treatment. Infliximab is reserved for severe refractory cases. We aimed to assess the impact of ICPI-induced diarrhea and colitis and their immunosuppressive treatment on patients' outcomes.
This retrospective analysis was conducted in 327 cancer patients who received ICPIs between 2011 and 2017. Patients with ICPI-induced toxicities in other organs were excluded. We collected data about patient demographics, clinical variables, and overall survival. We used descriptive analysis to compare different groups based on the occurrence and the treatment of diarrhea and colitis. Kaplan-Meier and log-rank test were used to estimate and compare overall survival durations between groups.
Diarrhea was recorded in 117 (36%) patients; 79 (24%) of them required immunosuppressive treatment of either systemic corticosteroid without infliximab (n = 44) or with infliximab (n = 35). Caucasian ethnicity, melanoma, stage 3 cancer, and ipilimumab were predictors of colitis that requires immunosuppression. Patients who required immunosuppressants had better overall survival than those who did not require treatment for colitis or diarrhea (P < 0.001). Immunosuppression for diarrhea or colitis did not affect the overall survival significantly (P = 0.232), nor did the choice of treatment (corticosteroids with vs. without infliximab; P = 0.768). Diarrhea was an independent predictor of a favorable overall survival (P < 0.001), irrespective of treatment need (P = 0.003). We confirmed the same results in a subgroup analysis for patients with stage IV malignancies only. Patients who received long duration of steroid treatment (> 30 days) had numerically higher infection rate than those who received steroid for shorter duration (40.4 vs. 25.8%, P = 0.160). Likewise, long duration of steroid without infliximab was associated with increased risk of infection compared to short duration of steroid with infliximab (42.9% vs. 14.3%, P = 0.089).
Patients with ICPI-induced diarrhea or colitis have improved survival outcomes. Diarrhea is an independent predictor of an improved survival regardless of treatment requirement. Immunosuppressive treatment for diarrhea did not significantly affect overall survival, however, infection rates were numerically higher among patients who received steroids for a long duration. Therefore, early non-steroid immunosuppressive therapy may ensure a more favorable overall outcome.
Therapies that produce deep and durable responses in patients with metastatic melanoma are needed. This phase II cohort from the international, single-arm PIVOT-02 study evaluated the ...CD122-preferential interleukin-2 pathway agonist bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in first-line metastatic melanoma.
A total of 41 previously untreated patients with stage III/IV melanoma received BEMPEG 0.006 mg/kg plus NIVO 360 mg once every 3 weeks for ≤ 2 years; 38 were efficacy-evaluable (≥ 1 postbaseline scan). Primary end points were safety and objective response rate (blinded independent central review); other end points included progression-free survival, overall survival (OS), and exploratory biomarkers.
At 29.0 months' median follow-up, the objective response rate was 52.6% (20 of 38 patients), and the complete response rate was 34.2% (13 of 38 patients). Median change in size of target lesions from baseline was -78.5% (response-evaluable population); 47.4% (18 of 38 patients) experienced complete clearance of target lesions. Median progression-free survival was 30.9 months (95% CI, 5.3 to not estimable). Median OS was not reached; the 24-month OS rate was 77.0% (95% CI, 60.4 to 87.3). Grade 3 and 4 treatment-related and immune-mediated adverse events occurred in 17.1% (7 of 41) and 4.9% (2 of 41) of patients, respectively. Increased polyfunctional responses in CD8+ and CD4+ T cells were seen in blood after treatment, driven by cytokines with effector functions. Early on-treatment blood biomarkers (CD8+ polyfunctional strength difference and eosinophils) correlated with treatment response.
BEMPEG in combination with NIVO was tolerated, with relatively low rates of grade 3 and 4 treatment-related and immune-mediated adverse events. The combination had encouraging antitumor activity in first-line metastatic melanoma, including an extended median progression-free survival. Exploratory analyses associated noninvasive, on-treatment biomarkers with response, before radiologic evidence was observed.
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