Comparing the rate of immunotherapy treatment change due to toxicity by sex.

BACKGROUND: Immuno-oncology therapy (IO) is associated with a variety of treatment-related toxicities. However, the impact of toxicity on the treatment discontinuation rate between males and females is unknown. We hypothesized that immune-related adverse events would lead to more frequent treatment changes in females since autoimmune diseases occur more frequently in females. AIMS: Our aim was to determine if there was a difference in the rate of immunotherapy treatment change due to toxicity between males and females. METHODS AND RESULTS: The Oncology Research Information Exchange Network Avatar Database collected clinical data from 10 United States cancer centers. Of 1035 patients receiving IO, 447 were analyzed, excluding those who did not have documentation noting if a patient changed treatment (n = 573). Fifteen patients with unknown or gender-specific cancer were excluded. All cancer types and stages were included. The primary endpoint was documented treatment change due to toxicity. Four hundred and forty-seven patients (281 males and 166 females) received IO treatment. The most common cancers treated were kidney, skin, and lung for 99, 84, and 54 patients, respectively. Females had a shorter IO course than males (median 3.7 vs. 5.1 months, respectively, p = .02). Fifty-four patients changed treatment due to toxicity. There was no significant difference between females and males on chi-square test (11.4% vs. 12.5%, respectively, p = 0.75) and multivariable logistic regression (OR 0.924, 95% CI 0.453-1.885, p = .827). Significantly more patients with chronic obstructive pulmonary disease (COPD) changed therapy due to toxicity (OR 2.491, 95% CI 1.025-6.054, p = .044). CONCLUSION: Females received a shorter course of IO than males. However, there was no significant difference in the treatment discontinuation rate due to toxicity between males and females receiving IO. Toxicity-related treatment change was associated with COPD.

Case Report: Dynamic overlap of melanoma, sarcoidosis, and targeted therapy for BRAF-mutant melanoma.

Targeted therapies, including BRAF and MEK inhibitors, are valuable treatment options for patients with unresectable or metastatic BRAF V600-mutant melanoma. With the improvement in survival seen with modern melanoma therapeutics, clinicians are learning the variable patterns associated with extended clinical courses. Sarcoidosis is characterized by non-caseating granulomatous inflammation of unknown etiology, often presenting with cutaneous, lung, or lymph node involvement. There is a known association between sarcoidosis and melanoma, and sarcoidosis is increasingly seen and described in the setting of anti-melanoma therapy. The challenge for clinicians is to differentiate between sarcoid-related and malignancy-related findings, which may follow a variable course over years. We present two cases of BRAF and MEK inhibitor-related sarcoidosis in patients with melanoma and review the literature. The dynamic nature of the clinical and radiographic findings impacted patient management and clinical decisions for years of their treatment course.

Relevance of the Updated Recursive Partitioning Analysis (U-RPA) Classification in the Contemporary Care of Patients with Brain Metastases.

Patients with brain metastases (BMETS) need information about the prognosis and potential value of treatment options to make informed therapeutic decisions, but tools to predict survival in contemporary practice are scarce. We propose an Updated Recursive Partitioning Analysis (U-RPA) instrument to predict survival and benefit from brain-directed treatment (BDT) of contemporary patients. This was a retrospective analysis of patients with BMETS treated between 2017 and 2019. With survival as the primary endpoint, we calculated the U-RPA and generated estimates using Kaplan-Meier curves and hazard ratios. Of 862 eligible patients, 752 received BDT and 110 received best supportive care (BSC). Median overall survival with BDT and BSC was 9.3 and 1.3 months, respectively. Patients in RPA class 1, 2A, 2B and 3 who underwent BDT had median survival of 28.1, 14.7, 7.6 and 3.3 months, respectively. The median survival for patients in RPA 3 who received BDT (n = 147), WBRT (n = 79) and SRS (n = 54) was 3.3, 2.9 and 4.1 months, respectively. The U-RPA defines prognosis estimates, independent of tumor type and treatment modality, which can assist to make value-based care treatment decisions. The prognosis for patients in U-RPA class 2B and 3 remains poor, with consideration for early palliative care involvement in these cases.

PD-L1 and MHC Class I Expression in High-grade Ovarian Cancers, Including Platinum-resistant Recurrences Treated With Checkpoint Inhibitor Therapy.

Immune-modulating therapies targeting the programmed cell death-1/programmed cell death ligand-1 (PD-L1) immunosuppressive system have been used successfully in many solid tumor types. There is evidence that biomarkers such as PD-L1 and major histocompatibility complex (MHC) class I help identify candidates for anti-programmed cell death-1/PD-L1 checkpoint inhibition, though the evidence is limited in ovarian malignancies. PD-L1 and MHC Class I immunostaining was performed on pretreatment whole tissue sections in 30 cases of high-grade ovarian carcinoma. The PD-L1 combined positive score was calculated (a score of ≥1 is considered positive). MHC class I status was categorized as an intact or subclonal loss. In patients who received immunotherapy, drug response was assessed using RECIST criteria. PD-L1 was positive in 26 of 30 cases (87%; combined positive score: 1 to 100). Seven of 30 patients showed subclonal loss of MHC class I (23%), and this occurred in both PD-L1 negative (3/4; 75%) and PD-L1 positive (4/26; 15%) cases. Only 1 of 17 patients who received immunotherapy in the setting of a platinum-resistant recurrence responded to the addition of immunotherapy, and all 17 died of disease. In the setting of recurrent disease, patients did not respond to immunotherapy regardless of PD-L1/MHC class I status, suggesting that these immunostains may not be effective predictive biomarkers in this setting. Subclonal loss of expression of MHC class I occurs in ovarian carcinoma, including in PD-L1 positive cases, suggesting that the 2 pathways of immune evasion may not be mutually exclusive and that it may be important to interrogate MHC class I status in PD-L1 positive tumors to identify additional immune evasion mechanisms in these tumors.

Multicenter Experience with Neoadjuvant Therapy in Melanoma Highlights Heterogeneity in Contemporary Practice.

OBJECTIVE: To determine the feasibility and impact of neoadjuvant therapy (NT) in patients who present with advanced melanoma amenable to surgical resection. SUMMARY BACKGROUND DATA: Given current effective systemic therapy for melanoma, the use of NT is being explored in patients with advanced melanoma with disease amenable to surgical resection. METHODS: Prospective data from 3 institutions was obtained in patients with clinically evident Stage III/IV melanoma who underwent NT. The primary objective was to compare recurrence-free survival between patients who had pathologic complete response (pCR) to those with persistent disease. RESULTS: NT was offered to 45 patients, with 43 patients initiating various NT regimens including PD-1 antagonist (PD-1) therapy (N = 16), PD-1 plus ipilimumab (N = 10), BRAF/MEK inhibitor therapy (N = 14), a combination of those three (N = 1), and talimogene laherparepvec (TVEC) (N = 2). Thirty-two (74.1%) patients underwent surgery whereas 11 patients did not undergo surgery for these reasons: clinical CR (N = 7), progressive disease not amenable to resection (N = 3), and ongoing therapy (N = 1). 12 of 32 patients (37.5%) had pCR with these therapies: PD-1 (N = 4), PD-1 plus ipilimumab (N = 2), BRAF/MEK (N = 4), combination (N = 1), and TVEC (N = 1). At median follow-up of 16.4 months there was only 1 recurrence in the pCR group and patients with a pCR had significantly improved recurrence-free survival compared to patients without pCR (p = 0.004). CONCLUSIONS: Despite variability in NT regimens across institutions, NT for melanoma is feasible and associated with improved prognosis in patients who achieve a pCR. Maximizing rates of pCR could improve prognosis for patients with advanced melanoma.

Phase I/II clinical trial of a helper peptide vaccine plus PD-1 blockade in PD-1 antibody-naïve and PD-1 antibody-experienced patients with melanoma (MEL64).

BACKGROUND: A vaccine containing 6 melanoma-associated peptides to stimulate helper T cells (6MHP) is safe, immunogenic, and clinically active. A phase I/II trial was designed to evaluate safety and immunogenicity of 6MHP vaccines plus programmed death 1 (PD-1) blockade. PARTICIPANTS AND METHODS: Participants with advanced melanoma received 6MHP vaccines in an incomplete Freund's adjuvant (6 vaccines over 12 weeks). Pembrolizumab was administered intravenously every 3 weeks. Tumor biopsies at baseline and day 22 were analyzed by multiplex immunohistochemistry. Primary end points were safety (Common Terminology Criteria for Adverse Events V.4.03) and immunogenicity (ex vivo interferon-γ ELISpot assay). Additional end points included changes in the tumor microenvironment (TME) and clinical outcomes. RESULTS: Twenty-two eligible participants were treated: 6 naïve to PD-1 antibody (Ab) and 16 PD-1 Ab-experienced. Median follow-up was 24.4 months. Most common treatment-related adverse events (any grade) included injection site reactions, fatigue, anemia, lymphopenia, fever, elevated aspartate aminotransferase, pruritus, and rash. Treatment-related dose-limiting toxicities were observed in 3 (14%) participants, which did not cross the study safety bound. A high durable T cell response (Rsp) to 6MHP was detected in only one participant, but twofold T cell Rsps to 6MHP were detected in 7/22 (32%; 90% CI (16% to 52%)) by week 13. Objective clinical responses were observed in 23% (1 complete response, 4 partial responses), including 4/6 PD-1 Ab-naïve (67%) and 1/16 PD-1 Ab-experienced (6%). Overall survival (OS) was longer for PD-1 Ab-naïve than Ab-experienced participants (HR 6.3 (90% CI (2.1 to 28.7)). In landmark analyses at 13 weeks, OS was also longer for those with T cell Rsps (HR 6.5 (90% CI (2.1 to 29.2)) and for those with objective clinical responses. TME evaluation revealed increased densities of CD8+ T cells, CD20+ B cells, and Tbet+ cells by day 22. CONCLUSIONS: Treatment with the 6MHP vaccine plus pembrolizumab was safe, increased intratumoral lymphocytes, and induced T cell Rsps associated with prolonged OS. The low T cell Rsp rate in PD-1 Ab-experienced participants corroborates prior murine studies that caution against delaying cancer vaccines until after PD-1 blockade. The promising objective response rate and OS in PD-1 Ab-naïve participants support consideration of a larger study in that setting.

Outcomes From Cytotoxic Chemotherapy Following Progression on Immunotherapy in Metastatic Melanoma: An Institutional Case-Series.

Introduction: The role of chemotherapy in the management of advanced melanoma is limited due to low response rates and short survival. Improved outcomes to chemotherapy administered after immunotherapy for metastatic melanoma and other solid tumors have been reported. We studied the outcomes of subjects treated at the University of Virginia (UVA) with chemotherapy following progression on prior systemic immunotherapy and compared the results with the existing literature. Materials and Methods: Subjects were identified through an institutional database of patients treated with immunotherapy at UVA. Demographic, pathologic and clinical factors were collected, along with dates of therapy, investigator-assessed best response as per Response Evaluation Criteria for Solid Tumors version 1.1 and dates of death or last follow up. Kaplan-Meier survival estimates and log-rank tests were used to perform time to event analysis of progression free survival and overall survival. Results: Forty-five patients were identified who met the inclusion criteria including 24 men and 21 women with a median age of 61 years. All patients had received at least one line of immunotherapy including 64.4% with prior anti-PD1 treatment. The cytotoxic chemotherapy regimens used included carboplatin with paclitaxel (55.6%), temozolomide (31.1%) and nab-paclitaxel (13.3%). The overall response rate for cytotoxic chemotherapy 22.2% and the disease control rate was 35.6%. The median progression-free survival was 1.7 months and median overall survival was 4.7 months. Nineteen (42.2%) patients survived greater than 6 months and seven (15.5%) patients survived over 12 months. Fourteen patients were able to proceed to further therapy. Discussion: Our results reveal that receipt of immunotherapy prior to chemotherapy for metastatic melanoma does not appear to improve the benefit of chemotherapy. The palliation of symptoms, maintenance of performance status and disease control may be valuable for some patients during this time of robust research and discovery for metastatic melanoma.

Multiple evanescent white dot syndrome-like reaction associated with ipilimumab and nivolumab immune checkpoint inhibitor therapy for metastasis of choroidal melanoma.

PURPOSE: To present a rare case of multiple evanescent white dot syndrome (MEWDS)-like presentation associated with immune checkpoint inhibitor therapy for metastatic choroidal melanoma. OBSERVATIONS: A 67-year-old non-myopic Caucasian female presented with bilateral worsening vision, flashes, and floaters after receiving two doses of ipilimumab and nivolumab for metastatic class 2 peripheral choroidal melanoma. Fundus imaging of the right eye revealed hypopigmented, extra-foveal scattered chorioretinal lesions with foveal granularity. Fluorescein angiogram and autofluorescence of the right eye demonstrated corresponding hyperfluorescent and hyperautofluorescent lesions in a wreath-like configuration. Optical coherence tomography of the right eye revealed subretinal fluid. Due to concurrent systemic side effects, checkpoint inhibitor therapy was paused and the patient was started on oral prednisone. At her one month follow up visit, her vision in her right eye returned to baseline and subretinal fluid resolved. CONCLUSIONS: This is the first reported case of a MEWDS-like chorioretinopathy after two cycles of ipilimumab/nivolumab therapy for metastatic choroidal melanoma. As immune checkpoint inhibitor therapy is still an evolving field, more research is needed to characterize ocular side effect profiles of these agents.

Phase I/II trial of a long peptide vaccine (LPV7) plus toll-like receptor (TLR) agonists with or without incomplete Freund's adjuvant (IFA) for resected high-risk melanoma.

BACKGROUND: We performed a clinical trial to evaluate safety and immunogenicity of a novel long peptide vaccine administered in combinations of incomplete Freund's adjuvant (IFA) and agonists for TLR3 (polyICLC) and TLR7/8 (resiquimod). We hypothesized that T cell responses to minimal epitope peptides (MEPs) within the long peptides would be enhanced compared with prior vaccines with MEP themselves and that T cell responses would be enhanced with TLR agonists, compared with IFA alone. METHODS: Participants with resected stage IIB-IV melanoma were vaccinated with seven long melanoma peptides (LPV7) from tyrosinase, gp100, MAGE-A1, MAGE-A10, and NY-ESO-1, each containing a known MEP for CD8+ T cells, plus a tetanus helper peptide (Tet) restricted by Class II MHC. Enrollment was guided by an adaptive design to one of seven adjuvant combinations. Vaccines were administered at weeks 1, 2, 3, 6, 9, 12 at rotating injection sites. T cell and IgG antibody (Ab) responses were measured with IFN-gamma ELIspot assay ex vivo and ELISA, respectively. RESULTS: Fifty eligible participants were assigned to seven study groups, with highest enrollment on arm E (LPV7+Tet+IFA+polyICLC). There was one dose-limiting toxicity (DLT) in Group E (grade 3 injection site reaction, 6% DLT rate). All other treatment-related adverse events were grades 1-2. The CD8+ T cell immune response rate (IRR) to MEPs was 18%, less than in prior studies using MEP vaccines in IFA. The CD8+ T cell IRR trended higher for IFA-containing adjuvants (24%) than adjuvants containing only TLR agonists (6%). Overall T cell IRR to full-length LPV7 was 30%; CD4+ T cell IRR to Tet was 40%, and serum Ab IRR to LPV7 was 84%. These IRRs also trended higher for IFA-containing adjuvants (36% vs 18%, 48% vs 24%, and 97% vs 60%, respectively). CONCLUSIONS: The LPV7 vaccine is safe with each of seven adjuvant strategies and induced T cell responses to CD8 MEPs ex vivo in a subset of patients but did not enhance IRRs compared with prior vaccines using short peptides. Immunogenicity was supported more by IFA than by TLR agonists alone and may be enhanced by polyICLC plus IFA. TRIAL REGISTRATION NUMBER: NCT02126579.

A phase 1 study of NY-ESO-1 vaccine + anti-CTLA4 antibody Ipilimumab (IPI) in patients with unresectable or metastatic melanoma.

Ipilimumab (IPI) can enhance immunity to the cancer-testis antigen NY-ESO-1. A clinical trial was designed to assess safety, immunogenicity, and clinical responses with IPI + NY-ESO-1 vaccines and effects on the tumor microenvironment (TME). Patients with measurable NY-ESO-1+ tumors were enrolled among three arms: A) IPI + NY-ESO-1 protein + poly-ICLC (pICLC) + incomplete Freund's adjuvant (IFA); B) IPI + NY-ESO-1 overlapping long peptides (OLP) + pICLC + IFA; and C) IPI + NY-ESO-1 OLP + pICLC. Clinical responses were assessed by irRC. T cell and Ab responses were assessed by ex vivo IFN-gamma ELIspot and ELISA. Tumor biopsies pre- and post-treatment were evaluated for immune infiltrates. Eight patients were enrolled: 5, 2, and 1 in Arms A-C, respectively. There were no DLTs. Best clinical responses were SD (4) and PD (4). T-cell and antibody (Ab) responses to NY-ESO-1 were detected in 6 (75%) and 7 (88%) patients, respectively, and were associated with SD. The breadth of Ab responses was greater for patients with SD than PD (p = .036). For five patients evaluable in the TME, treatment was associated with increases in proliferating (Ki67+) CD8+ T cells and decreases in RORγt+ CD4+ T cells. T cell densities increased for those with SD. Detection of T cell responses to NY-ESO-1 ex vivo in most patients suggests that IPI may have enhanced those responses. Proliferating intratumoral CD8+ T cells increased after vaccination plus IPI suggesting favorable impact of IPI plus NY-ESO-1 vaccines on the TME. List of Abbreviations: Ab = antibody; CTCAE = NCI Common Terminology Criteria for Adverse Events; DHFR/DHRP = dihydrofolate reductase; DLT = Dose-limiting toxicity; ELISA = enzyme-linked immunosorbent assay; IFA = incomplete Freund's adjuvant (Montanide ISA-51); IFNγ = Interferon gamma; IPI = Ipilimumab; irRC = immune-related response criteria; mIFH = multispectral immunofluorescence histology; OLP = NY-ESO-1 overlapping long peptides; PBMC = peripheral blood mononuclear cells; PD = Progressive disease; pICLC = poly-ICLC (Hiltonol), a TLR3/MDA-5 agonist; RLT = Regimen-limiting Toxicity; ROI = regions of interest; RT = room temperature; SAE = serious adverse event; SD = stable disease; TEAE = treatment-emergent adverse events; TLR = toll-like receptor; TME = tumor microenvironment; TRAE = treatment-related adverse events.

Trial to evaluate the immunogenicity and safety of a melanoma helper peptide vaccine plus incomplete Freund's adjuvant, cyclophosphamide, and polyICLC (Mel63).

BACKGROUND: Peptide vaccines designed to stimulate melanoma-reactive CD4+ T cells can induce T cell and antibody (Ab) responses, associated with enhanced overall survival. We hypothesized that adding toll-like receptor 3 agonist polyICLC to an incomplete Freund's adjuvant (IFA) would be safe and would support strong, durable CD4+ T cell and Ab responses. We also hypothesized that oral low-dose metronomic cyclophosphamide (mCy) would be safe, would reduce circulating regulatory T cells (T-regs) and would further enhance immunogenicity. PARTICIPANTS AND METHODS: An adaptive design based on toxicity and durable CD4+ T cell immune response (dRsp) was used to assign participants with resected stage IIA-IV melanoma to one of four study regimens. The regimens included a vaccine comprising six melanoma peptides restricted by Class II MHC (6MHP) in an emulsion with IFA alone (Arm A), with IFA plus systemic mCy (Arm B), with IFA+ local polyICLC (Arm C), or with IFA+ polyICLC+ mCy (Arm D). Toxicities were recorded (CTCAE V.4.03). T cell responses were measured by interferon γ ELIspot assay ex vivo. Serum Ab responses to 6MHP were measured by ELISA. Circulating T-regs were assessed by flow cytometry. RESULTS: Forty-eight eligible participants were enrolled and treated. Early data on safety and dRsp favored enrollment on arm D. Total enrollment on Arms A-D were 3, 7, 6, and 32, respectively. Treatment-related dose-limiting toxicities (DLTs) were observed in 1/7 (14%) participants on arm B and 2/32 (6%) on arm D. None exceeded the 25% DLT threshold for early closure to enrollment for any arm. Strong durable T cell responses to 6MHP were detected ex vivo in 0%, 29%, 67%, and 47% of participants on arms A-D, respectively. IgG Ab responses were greatest for arms C and D. Circulating T-regs frequencies were not altered by mCy. CONCLUSIONS: 6MHP vaccines administered with IFA, polyICLC, and mCy were well tolerated. The dRsp rate for arm D of 47% (90% CI 32 to 63) exceeded the 18% (90% CI 11 to 26) rate previously observed with 6MHP in IFA alone. Vaccination with IFA+ polyICLC (arm C) also showed promise for enhancing T cell and Ab responses.

Genesis of Quality Measurements to Improve the Care Delivered to Patients With Brain Metastases.

PURPOSE: High-value and high-quality health care requires outcome measurements to inform treatment decisions, but, to our knowledge, no standardized measurements exist to evaluate brain metastases (BMs) care. We propose a set of measurements and report on their implementation in the care of patients with BMs. METHODS: On the basis of a stakeholders' needs assessment and review of the literature, we identified outcome and process measurements to assess the care of patients with BMs according to treatment modality. Retrospectively, we applied these indicators of care to all patients diagnosed and treated at our institution over 2 years. RESULTS: We ascertained 5 outcome and 6 process measurements of relevance in the care of BMs. When applied to 209 patients (89.7%) who received cancer treatment, 77% were alive > 90 days after diagnosis. The proportion alive at 90 days after surgery, whole-brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS) was 82%, 59%, and 81%, respectively. Other performance measurements included 30-day postoperative readmission rate (6%), SRS within 30 days of surgery (79%), use of memantine with WBRT (41%), advance directives within 6 months of diagnosis (53%), and palliative care consultation for patients with poor prognosis or receiving WBRT (45%). Measurements for the 24 patients (10.3%) receiving best supportive care were advance directives documentation (67%) and referral to palliative or hospice care (83%). CONCLUSION: We propose a set of measurements to apprise quality improvement efforts, inform treatment decision-making, and to use in evaluation of the performance of interdisciplinary BMs programs. Their refinement can potentially enhance the quality and value of care delivered to patients with BMs.

Severe combined cardiac and neuromuscular toxicity from immune checkpoint blockade: an institutional case series.

BACKGROUND: Immune checkpoint inhibition is part of standard systemic management for many advanced malignancies. Toxicities from this treatment approach are unpredictable, though usually reversible with management per established guidelines. Some patients suffer major morbidity and treatment-related mortality from these agents in an unpredictable manner. Cardiac and neurologic complications are rare, but can result in serious clinical consequences. METHODS: We describe the presentation, management, and outcomes of eight sequential cases of combined cardiac and neurologic toxicities resulting in severe illness and demonstrating lack of rapid response to immunosuppression. RESULTS: Our cohort consisted of six males and two females with an average age of 73.5 years (61-89 years). There were four patients with melanoma, and one patient each with urothelial carcinoma, renal cell carcinoma, breast cancer, and non-small cell lung cancer. Four patients received combination immunotherapy and four patients received monotherapy. The median time to presentation from treatment initiation was 27 days (11-132 days). All patients had a cardiovascular and neurologic toxicity, and most had hepatitis and myositis. The cardiac signs and symptoms were the prominent initial features of the clinical presentation. Each patient was managed by a multidisciplinary team and received a range of immunosuppressive agents. All patients died as a consequence of the immune related adverse events. CONCLUSIONS: The evaluation of patients with cardiac adverse events from immunotherapy, should include assessment of overlapping toxicities such as myasthenia gravis and myositis. Providers should be aware of the potential for an extended duration of disability and slow improvement for certain toxicities as these expectations may factor prominently in goals of care decisions.

MHC-restricted phosphopeptide antigens: preclinical validation and first-in-humans clinical trial in participants with high-risk melanoma.

BACKGROUND: Phosphorylated peptides presented by MHC molecules represent a new class of neoantigens expressed on cancer cells and recognized by CD8 T-cells. These peptides are promising targets for cancer immunotherapy. Previous work identified an HLA-A*0201-restricted phosphopeptide from insulin receptor substrate 2 (pIRS2) as one such target. The purpose of this study was to characterize a second phosphopeptide, from breast cancer antiestrogen resistance 3 (BCAR3), and to evaluate safety and immunogenicity of a novel immunotherapic vaccine comprising either or both of these phosphorylated peptides. METHODS: Phosphorylated BCAR3 protein was evaluated in melanoma and breast cancer cell lines by Western blot, and recognition by T-cells specific for HLA-A*0201-restricted phosphorylated BCAR3 peptide (pBCAR3126-134) was determined by 51Cr release assay and intracellular cytokine staining. Human tumor explants were also evaluated by mass spectrometry for presentation of pIRS2 and pBCAR3 peptides. For the clinical trial, participants with resected stage IIA-IV melanoma were vaccinated 6 times over 12 weeks with one or both peptides in incomplete Freund's adjuvant and Hiltonol (poly-ICLC). Adverse events (AEs) were coded based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V.4.03, with provision for early study termination if dose-limiting toxicity (DLT) rates exceeded 33%. The enrollment target was 12 participants evaluable for immune response to each peptide. T-cell responses were assessed by interferon-γ ELISpot assay. RESULTS: pBCAR3 peptides were immunogenic in vivo in mice, and in vitro in normal human donors, and T-cells specific for pBCAR3126-134 controlled outgrowth of a tumor xenograft. The pIRS21097-1105 peptide was identified by mass spectrometry from human hepatocellular carcinoma tumors. In the clinical trial, 15 participants were enrolled. All had grade 1 or 2 treatment-related AEs, but there were no grade 3-4 AEs, DLTs or deaths on study. T-cell responses were induced to the pIRS21097-1105 peptide in 5/12 patients (42%, 90% CI 18% to 68%) and to the pBCAR3126-134 peptide in 2/12 patients (17%, 90% CI 3% to 44%). CONCLUSION: This study supports the safety and immunogenicity of vaccines containing the cancer-associated phosphopeptides pBCAR3126-134 and pIRS21097-1105, and the data support continued development of immune therapy targeting phosphopeptides. Future studies will define ways to further enhance the magnitude and durability of phosphopeptide-specific immune responses. TRIAL REGISTRATION NUMBER: NCT01846143.

A multipeptide vaccine plus toll-like receptor agonists LPS or polyICLC in combination with incomplete Freund's adjuvant in melanoma patients.

BACKGROUND: Cancer vaccines require adjuvants to induce effective immune responses; however, there is no consensus on optimal adjuvants. We hypothesized that toll-like receptor (TLR)3 agonist polyICLC or TLR4 agonist lipopolysaccharide (LPS), combined with CD4 T cell activation, would support strong and durable CD8+ T cell responses, whereas addition of an incomplete Freund's adjuvant (IFA) would reduce magnitude and persistence of immune responses. PATIENTS AND METHODS: Participants with resected stage IIB-IV melanoma received a vaccine comprised of 12 melanoma peptides restricted by Class I MHC (12MP), plus a tetanus helper peptide (Tet). Participants were randomly assigned 2:1 to cohort 1 (LPS dose-escalation) or cohort 2 (polyICLC). Each cohort included 3 subgroups (a-c), receiving 12MP + Tet + TLR agonist without IFA (0), or with IFA in vaccine one (V1), or all six vaccines (V6). Toxicities were recorded (CTCAE v4). T cell responses were measured with IFNγ ELIspot assay ex vivo or after one in vitro stimulation (IVS). RESULTS: Fifty-three eligible patients were enrolled, of which fifty-one were treated. Treatment-related dose-limiting toxicities (DLTs) were observed in 0/33 patients in cohort 1 and in 2/18 patients in cohort 2 (11%). CD8 T cell responses to 12MP were detected ex vivo in cohort 1 (42%) and in cohort 2 (56%) and in 18, 50, and 72% for subgroups V0, V1, and V6, respectively. T cell responses to melanoma peptides were more durable and of highest magnitude for IFA V6. CONCLUSIONS: LPS and polyICLC are safe and effective vaccine adjuvants when combined with IFA. Contrary to the central hypothesis, IFA enhanced T cell responses to peptide vaccines when added to TLR agonists. Future studies will aim to understand mechanisms underlying the favorable effects with IFA. TRIAL REGISTRATION: The clinical trial Mel58 was performed with IRB (#15781) and FDA approval and is registered with Clinicaltrials.gov on April 25, 2012 (NCT01585350). Patients provided written informed consent to participate. Enrollment started on June 24, 2012.

Quantitative Spatial Profiling of PD-1/PD-L1 Interaction and HLA-DR/IDO-1 Predicts Improved Outcomes of Anti-PD-1 Therapies in Metastatic Melanoma.

Purpose: PD-1/L1 axis-directed therapies produce clinical responses in a subset of patients; therefore, biomarkers of response are needed. We hypothesized that quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti-PD-1 response.Experimental Design: Pretreatment tumor biopsies from 166 patients treated with anti-PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery (n = 24) and validation (n = 142) cohorts. Biomarker-positive cells and their colocalization were spatially profiled in pathologist-selected tumor regions using novel Automated Quantitative Analysis algorithms. Selected biomarker signatures, PD-1/PD-L1 interaction score, and IDO-1/HLA-DR coexpression were evaluated for anti-PD-1 treatment outcomes.Results: In the discovery cohort, PD-1/PD-L1 interaction score and/or IDO-1/HLA-DR coexpression was strongly associated with anti-PD-1 response (P = 0.0005). In contrast, individual biomarkers (PD-1, PD-L1, IDO-1, HLA-DR) were not associated with response or survival. This finding was replicated in an independent validation cohort: patients with high PD-1/PD-L1 and/or IDO-1/HLA-DR were more likely to respond (P = 0.0096). These patients also experienced significantly improved progression-free survival (HR = 0.36; P = 0.0004) and overall survival (HR = 0.39; P = 0.0011). In the combined cohort, 80% of patients exhibiting higher levels of PD-1/PD-L1 interaction scores and IDO-1/HLA-DR responded to PD-1 blockers (P = 0.000004). In contrast, PD-L1 expression was not predictive of survival.Conclusions: Quantitative spatial profiling of key tumor-immune suppression pathways by novel digital pathology algorithms could help more reliably select melanoma patients for PD-1 monotherapy. Clin Cancer Res; 24(21); 5250-60. ©2018 AACR.

Primary Cutaneous Small/Medium CD4+ T-CELL Lymphoproliferative Disorder Occurring in a Patient With Metastatic Melanoma.

Therapeutic agents designed to stimulate the immune system are now cornerstones in the treatment of metastatic melanoma. These drugs promote lymphocyte growth and survival, which could plausibly result in clinical lymphoproliferative disorders. We report the case of a 62-year-old female with metastatic melanoma who developed primary cutaneous small/medium CD4 T-cell lymphoproliferative disorder (PC-SMTCL) after treatment with vemurafenib and recombinant high-dose interleukin-2 (IL-2). The patient developed a painless red papule behind the ear. A biopsy showed a dense population of CD4 lymphocytes with a T-follicular helper cell phenotype. Molecular studies confirmed the presence of a clonal population of T cells, and the process was classified as PC-SMTCL. The patient was diagnosed with metastatic melanoma approximately 3 years before the development of the cutaneous lymphoma and had been treated with vemurafenib followed by 2 courses of IL-2. The patient's last course of IL-2 was completed in April of 2013. She developed the cutaneous lymphoma behind her ear in December of 2015. An association between PC-SMTCL and vemurafenib treatment for advanced melanoma has been reported previously in one patient; however, an association between PC-SMTCL and IL-2 treatment has not been documented. The immunostimulatory properties of IL-2 or vemurafenib may be responsible for the development of PC-SMTCL in our patient. Additionally, antigenic stimulation of the immune system by melanoma itself could contribute to clonal selection of lymphocytes.

Regression of an intramedullary spinal cord metastasis with a checkpoint inhibitor: a case report.

Intramedullary spinal cord metastasis is an increasingly common diagnosis in patients with cancer largely owing to new imaging techniques and the increase lifespan of patients with malignant tumors. The diagnosis confers significant morbidity and a poor prognosis. Mainstay palliative treatment options include corticosteroids, fractionated radiotherapy and surgery in select cases. In the modern era of immunotherapy for the treatment of several tumor types, the efficacy of these agents against parenchymal CNS tumors remains unanswered. Here, we report a case of regression of an intramedullary spinal cord metastasis with a checkpoint inhibitor.