Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the ...results of an ongoing phase II clinical trial testing the efficacy of ACT using TIL in patients with metastatic melanoma and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response.
Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL, followed by two cycles of high-dose interleukin (IL)-2 therapy. The effects of patient clinical features and the phenotypes of the T cells infused on the clinical response were determined.
Overall, 15 of 31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC) with 2 patients (6.5%) having a complete response. Progression-free survival of more than 12 months was observed for 9 of 15 (60%) of the responding patients. Factors significantly associated with the objective tumor regression included a higher number of TIL infused, a higher proportion of CD8(+) T cells in the infusion product, a more differentiated effector phenotype of the CD8(+) population, and a higher frequency of CD8(+) T cells coexpressing the negative costimulation molecule "B- and T-lymphocyte attenuator" (BTLA). No significant difference in the telomere lengths of TIL between responders and nonresponders was identified.
These results indicate that the immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in patients with metastatic melanoma and that CD8(+) T cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression.
Background
Given the rapidly evolving nature of the field, the current state of “high-risk” head and neck cutaneous squamous cell carcinoma (HNcSCC) is poorly characterized.
Methods
Narrative review ...of the epidemiology, diagnosis, workup, risk stratification, staging and treatment of high-risk HNcSCC.
Results
Clinical and pathologic risk factors for adverse HNcSCC outcomes are nuanced (e.g., immunosuppression and perineural invasion). Frequent changes in adverse prognosticators have outpaced population-based registries and the variables they track, restricting our understanding of the epidemiology of HNcSCC and inhibiting control of the disease. Current heterogeneous staging and risk stratification systems are largely derived from institutional data, compromising their external validity. In the absence of staging system consensus, tumor designations such as “high risk” and “advanced” are variably used and insufficiently precise to guide management. Evidence guiding treatment of high-risk HNcSCC with curative intent is also suboptimal. For patients with incurable disease, an array of trials are evaluating the impact of immunotherapy, targeted biologic therapy, and other novel agents.
Conclusion
Population-based registries that broadly track updated, nuanced, adverse clinicopathologic risk factors, and outcomes are needed to guide development of improved staging systems. Design and development of randomized controlled trials (RCTs) in advanced-stage HNcSCC populations are needed to evaluate (1) observation, sentinel lymph node biopsy, or elective neck dissection for management of the cN0 neck, (2) indications for surgery plus adjuvant radiation versus adjuvant chemoradiation, and (3) the role of immunotherapy in treatment with curative intent. Considering these knowledge gaps, the authors explore a potential high-risk HNcSCC treatment framework.
HDIL-2 is approved for advanced melanoma based on its durable antitumor activity. MAGE-A3 cancer immunotherapeutic (MAGE-A3 CI) is a recombinant MAGE-A3 protein combined with an immunostimulant ...adjuvant system and has shown antitumor activity in melanoma. We assessed the safety and anti-tumor activity of HDIL-2 combined with MAGE-A3 CI in advanced melanoma.
Patients with unresectable Stage III or Stage IV MAGE-A3-positive melanoma were enrolled in this phase II study. Treatment included an induction phase of MAGE-A3 CI plus HDIL-2 for 8 cycles followed by a maintenance phase of MAGE-A3 CI monotherapy. The primary endpoints were safety and objective response assessed per RECIST v1.1. Immune biomarker and correlative studies on tumor and peripheral blood were performed.
Eighteen patients were enrolled. Seventeen patients were evaluable for safety and sixteen for response. Responses occurred in 4/16 (25%) patients with 3 complete responses, and stable disease in 6/16 (38%) patients with a disease control rate of 63%. The median duration of response was not reached at median follow-up of 36.8 months. Induction therapy of HDIL-2 + MAGE-A3 CI had similar toxicities to those reported with HDIL-2 alone. Maintenance MAGE-A3 monotherapy was well-tolerated. Increased immune checkpoint receptor expression by circulating T regulatory cells was associated with poor clinical outcomes; and responders tended to have increased tumor infiltrating T cells in the baseline tumor samples.
The safety profile of HDIL-2 + MAGE-A3 CI was similar to HDIL-2 monotherapy. Maintenance MAGE-A3 CI provides robust anti-tumor activity in patients who achieved disease control with induction therapy. Immune monitoring data suggest that MAGE-A3 CI plus checkpoint inhibitors could be a promising treatment for MAGE-A3-positive melanoma.
ClinicalTrials.gov, NCT01266603 . Registered 12/24/2010, https://clinicaltrials.gov/ct2/show/NCT01266603.
A useful clinical biomarker requires not only association but also a consistent temporal relationship. For instance, chemotherapy-induced neutropenia and epidermal growth-factor inhibitor-related ...acneiform rash both occur within weeks of treatment initiation, thereby providing information prior to efficacy assessment. Although immune checkpoint inhibitor (ICI)-associated immune-related adverse events (irAE) have been associated with therapeutic benefit, irAE may have delayed and highly variable onset. To determine whether ICI efficacy and irAE could serve as clinically useful biomarkers for predicting each other, we determined the temporal relationship between initial efficacy assessment and irAE onset in a diverse population treated with ICI.
Using two-sided Fisher exact and Cochran-Armitage tests, we determined the relative timing of initial efficacy assessment and irAE occurrence in a cohort of 155 ICI-treated patients (median age 68 years, 40% women).
Initial efficacy assessment was performed a median of 50 days interquartile range (IQR) 39-59 days after ICI initiation; median time to any irAE was 77 days (IQR 28-145 days) after ICI initiation. Median time to first irAE was 42 days (IQR 20-88 days). Overall, 58% of any irAE and 47% of first irAE occurred after initial efficacy assessment. For clinically significant (grade ≥2) irAE, 60% of any and 53% of first occurred after initial efficacy assessment. The likelihood of any future irAE did not differ according to response (45% for complete or partial response vs. 47% for other cases;
=1). In landmark analyses controlling for clinical and toxicity follow-up, patients demonstrating greater tumor shrinkage at initial efficacy assessment were more likely to develop future grade ≥2 (
=0.05) and multi-organ (
=0.02) irAE.
In contrast to that seen with chemotherapy and molecularly targeted therapies, the temporal relationship between ICI efficacy and toxicity is complex and bidirectional. In practice, neither parameter can be routinely relied on as a clinical biomarker to predict the other.
We determined the relationship between symptom severity and distress for multiple cancer symptoms, and examined patient demographic influences on severity and distress in advanced cancer. A ...Cochran—Armitage trend test determined whether symptom distress increased with severity. Chi-square, Fisher’s exact test and logistic regression analysis examined moderate/severe (‘clinically important’) and distressful symptoms by age (≤65 versus >65), gender, primary site group, and ECOG performance status. Forty-six symptoms were analyzed in 181 individuals. More than 50% of individuals with clinically important symptoms rated them as distressful. The median percentage of individuals with mild but still distressful symptoms was 25%, with a range of 0% (bad dreams) to 73% (sore mouth). In both univariate and multivariate analysis, younger (≤65 years) patients, females, and those with poor performance status had more clinically important and a higher prevalence of distressful symptoms (only anxiety was more frequently distressful to older individuals). Clinically important symptoms and two of those considered distressful varied by primary site group. After control for severity, symptom distress did not differ by primary site group. The prevalence of distress increased with greater symptom severity. Younger individuals, those with poor performance status, and females had greater symptom severity and distress. Mild symptoms were often distressful. After adjustment for severity, age, gender, and performance status all influenced symptom distress.
This study examined symptoms reported by patients after open-ended questioning vs those systematically assessed using a 48-question survey.
Consecutive patients referred to the palliative medicine ...program at the Cleveland Clinic Foundation were screened. Open-ended questions were asked initially followed by a 48-item investigator-developed symptom checklist. Each symptom was rated for severity as mild, moderate, or severe. Symptom distress was also evaluated. Data were collected using standardized pre-printed forms.
Two hundred and sixty-five patients were examined and 200 were eligible for assessment. Of those assessed, the median age was 65 years (range 17-90), and median ECOG performance status was 2 (range 1-4). A total of 2,397 symptoms were identified, 322 volunteered and 2,075 by systematic assessment. The median number of volunteered symptoms was one (range zero to six). Eighty-three percent of volunteered symptoms were moderate or severe and 17% mild. Ninety-one percent were distressing. Fatigue was the most common symptom identified by systematic assessment but pain was volunteered most often. The median number of symptoms found using systematic assessment was ten (0-25). Fifty-two percent were rated moderate or severe and 48% mild. Fifty-three percent were distressing. In total, 69% of 522 severe symptoms and 79% of 1,393 distressing symptoms were not volunteered. Certain symptoms were more likely to be volunteered; this was unaffected by age, gender, or race.
The median number of symptoms found using systematic assessment was tenfold higher (p<0.001) than those volunteered. Specific detailed symptom inquiry is essential for optimal palliation in advanced disease.
•We retrospectively analyzed baseline and post-treatment cytokines and autoantibody levels in patients undergoing immune check-point inhibitor (ICI) immunotherapy.•The effect of radiation therapy ...(RT) was assessed by dividing the cohorts into those who received RT prior to ICI and those who did not.•We identified few differences in systemic immune parameters according to prior RT.•Complement C8 antibody and CX3CL1 levels were higher in patients with prior RT.
Preclinical studies have demonstrated the ability of radiation therapy (RT) to augment immune response and tumor control by immune checkpoint inhibitors (ICI). However, numerous clinical trials combining RT and ICI have yielded relatively disappointing results. To improve understanding of optimal use of these therapies, we assessed systemic immune effects of prior RT in patients receiving ICI.
Pre- and post-ICI blood samples were collected from patients enrolled in a prospective immunotherapy biospecimen protocol. Mutiplex panels of 40 cytokines and 120 autoantibodies (Ab) were analyzed. We identified differences in these parameters according to receipt, timing, and type of prior RT. We calculated P values using the Pearson product-moment correlation coefficient and false discovery rate (FDR) using the Benjamini-Hochberg Procedure.
Among 277 total patients, 69 (25%) received RT in the 6 months prior to ICI initiation. Among RT-treated patients, 23 (33%) received stereotactic RT, and 33 (48%) received curative intent RT. There was no significant difference in demographics or type of immunotherapy between patients according to prior RT exposure. Baseline complement C8 Ab and MIP-1d/CCL15 were significantly higher among patients with prior RT. For MIP-1d/CCL15, only prior stereotactic RT was associated with significant differences.
Prior RT is associated with few changes in systemic immune parameters in patients receiving ICI. The underlying mechanisms and optimal approach to harnessing the potential synergy of RT and ICI require further prospective clinical investigation.
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Antibiotic administration is associated with worse clinical outcomes and changes to the gut microbiome in cancer patients receiving immune checkpoint inhibitors (ICI). However, the effects of ...antibiotics on systemic immune function are unknown. We, therefore, evaluated antibiotic exposure, therapeutic responses, and multiplex panels of 40 serum cytokines and 124 antibodies at baseline and six weeks after ICI initiation, with p < 0.05 and false discovery rate (FDR) < 0.2 considered significant. A total of 251 patients were included, of whom the 135 (54%) who received antibiotics had lower response rates and shorter survival. Patients who received antibiotics prior to ICI initiation had modestly but significantly lower baseline levels of nucleolin, MDA5, c-reactive protein, and liver cytosol antigen type 1 (LC1) antibodies, as well as higher levels of heparin sulfate and Matrigel antibodies. After ICI initiation, antibiotic-treated patients had significantly lower levels of MDA5, CENP.B, and nucleolin antibodies. Although there were no clear differences in cytokines in the overall cohort, in the lung cancer subset (53% of the study population), we observed differences in IFN-γ, IL-8, and macrophage inflammatory proteins. In ICI-treated patients, antibiotic exposure is associated with changes in certain antibodies and cytokines. Understanding the relationship between these factors may improve the clinical management of patients receiving ICI.
Gastrointestinal stromal tumors (GIST) are the most common type of soft tissue sarcoma that occur throughout the gastrointestinal tract. Most of these tumors are caused by oncogenic activating ...mutations in the KIT or PDGFRA genes. The NCCN Guidelines for GIST provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with these tumors. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised systemic therapy options for unresectable, progressive, or metastatic GIST based on mutational status, and updated recommendations for the management of GIST that develop resistance to specific tyrosine kinase inhibitors.
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