Dendritic cell vaccines targeting tumor blood vessel antigens in combination with dasatinib induce therapeutic immune responses in patients with checkpoint-refractory advanced melanoma

BackgroundA first-in-human, randomized pilot phase II clinical trial combining vaccines targeting overexpressed, non-mutated tumor blood vessel antigens (TBVA) and tyrosine kinase inhibitor dasatinib was conducted in human leukocyte antigen (HLA)-A2+ patients with advanced melanoma.MethodsPatient monocyte-derived type-1-polarized dendritic cells were loaded with HLA-A2-presented peptides derived from TBVA (DLK1, EphA2, HBB, NRP1, RGS5, TEM1) and injected intradermally as a vaccine into the upper extremities every other week. Patients were randomized into one of two treatment arms receiving oral dasatinib (70 mg two times per day) beginning in week 5 (Arm A) or in week 1 (Arm B). Trial endpoints included T cell response to vaccine peptides (interferon-γ enzyme-linked immunosorbent spot), objective clinical response (Response Evaluation Criteria in Solid Tumors V.1.1) and exploratory tumor, blood and serum profiling of immune-associated genes/proteins.ResultsSixteen patients with advanced-stage cutaneous (n=10), mucosal (n=1) or uveal (n=5) melanoma were accrued, 15 of whom had previously progressed on programmed cell death protein 1 (PD-1) blockade. Of 13 evaluable patients, 6 patients developed specific peripheral blood T cell responses against ≥3 vaccine-associated peptides, with further evidence of epitope spreading. All six patients with specific CD8+ T cell response to vaccine-targeted antigens exhibited evidence of T cell receptor (TCR) convergence in association with preferred clinical outcomes (four partial response and two stabilization of disease (SD)). Seven patients failed to respond to vaccination (one SD and six progressive disease). Patients in Arm B (immediate dasatinib) outperformed those in Arm A (delayed dasatinib) for immune response rate (IRR; 66.7% vs 28.6%), objective response rate (ORR) (66.7% vs 0%), overall survival (median 15.45 vs 3.47 months; p=0.0086) and progression-free survival (median 7.87 vs 1.97 months; p=0.063). IRR (80% vs 25%) and ORR (60% vs 12.5%) was greater for females versus male patients. Tumors in patients exhibiting response to treatment displayed (1) evidence of innate and adaptive immune-mediated inflammation and TCR convergence at baseline, (2) on-treatment transcriptional changes associated with reduced hypoxia/acidosis/glycolysis, and (3) increased inflammatory immune cell infiltration and tertiary lymphoid structure neogenesis.ConclusionsCombined vaccination against TBVA plus dasatinib was safe and resulted in coordinating immunologic and/or objective clinical responses in 6/13 (46%) evaluable patients with melanoma, particularly those initiating treatment with both agents.Trial registration numberNCT01876212.

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Clinical Effectiveness of Combination Immunotherapy DPX-Survivac, Low Dose Cyclophosphamide, and Pembrolizumab in Recurrent/Refractory DLBCL: The Spirel Study

Blood ◽

10.1182/blood-2020-136751 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 16-16

Author(s):

Neil L Berinstein ◽

Isabelle Bence-Bruckler ◽

Nicholas Allen Forward ◽

Pierre Laneuville ◽

Joy Mangel ◽

...

Keyword(s):

T Cell ◽

Cell Carcinoma ◽

Board Of Directors ◽

Cell Response ◽

Research Funding ◽

Low Dose ◽

Response Rate ◽

Objective Response ◽

T Cell Response ◽

Advisory Committees

Background: Recurrent/refractory (r/r) DLBCL presents a major treatment challenge, especially in the setting of patients who are ineligible for, or relapsing after, potentially curative treatments such as autologous stem cell transplant (ASCT) and chimeric antigen receptor T cell (CAR-T) therapy. Efficacious treatment options that are well-tolerated and easily accessible in this population represent a critical unmet medical need. DPX-Survivac is a targeted T cell activation therapy against cancers expressing survivin. Survivin plays an essential role in cancer biology and represents a target of choice to disrupt tumour progression. DPX-Survivac's mechanism of action relies on its ability to generate robust and durable survivin-specific T cells that migrate to, infiltrate and kill tumour cells. DPX-Survivac is administered with intermittent, low dose cyclophosphamide (CPA) used as an immunomodulator. In nonclinical studies, treatment with DPX-Survivac increases PD-L1 and PD-1 expression providing the rationale for combination with pembrolizumab. Methods: "SPiReL" is a Phase 2 non-randomized, open label, efficacy and safety study. Subjects with r/r DLBCL with confirmed survivin expression are eligible for participation. Subjects must also be ineligible for potentially curative therapy. The treatment and testing regimen is shown in the figre below. The primary objective of SPiReL is to document a minimum Objective Response Rate (ORR) of 24% (in 6/25 subjects) using the modified Cheson criteria (2007). Secondary objectives include safety, duration of response and time to next treatment. Exploratory endpoints include T cell response, tumour immune cell infiltration, and biomarker analysis. Results: At data cut-off, 22 subjects have been enrolled in the study. The median age is 75.5 years (50-82). Thirteen of 22 subjects (59.1%) are GCB sub-type, 8 subjects (36.4%) are non-GCB and 1 subject (4.5%) has primary cutaneous DLBCL, leg type. The median number of prior therapies is 2 (1-7), with 4 subjects having previously undergone ASCT and 5 subjects with transformed disease. Of the 22 enrolled subjects, 8 are not evaluable per protocol for clinical efficacy due to early disease progression. Four subjects are active on treatment, 3 of which have not yet reached the first time point for assessment. Clinical outcome was analyzed for the Full Analysis Set (FAS) (n=19) and in the Per Protocol (PP) analysis (n=11). Of 11 subjects in the PP, 7 subjects (63.6%) have achieved an objective response, meeting the study's primary endpoint; 3 subjects (27.3%) with a CR and 4 subjects (36.4%) with a PR. Three subjects (27.3%) achieved SD and thus clinical benefit was demonstrated in 10/11 (90.9%) of evaluable subjects. Two subjects (18.2%) have completed the 1 year treatment period, 8 subjects (72.7%) discontinued treatment due to disease progression, and 1 subject (9.2%) discontinued treatment due to an unrelated Adverse Event (AE). Including the entire FAS, the objective response rate was 7/19 (36.8%). This treatment combination is well-tolerated, only 11% of Treatment Related AEs (TRAEs) were assessed as Grade 3 or higher. The majority of the Grade 1 and 2 TRAEs were Injection Site Reactions (ISRs) related to DPX-Survivac. Ten serious AEs were reported, of which 3 were considered related to study treatment. No subjects have discontinued study treatment due to a TRAE. Analyses of peripheral blood T cell responses to survivin by ELISpot assay shows that 7/7 subjects who achieved an objective response have survivin-specific T cell response. One subject with PD also showed a survivin-specific T cell response, supporting the mechanism of action and the role of DPX-Survivac in anti-tumor activity. Summary: DPX-Survivac and low dose CPA in combination with pembrolizumab, demonstrates promising clinical activity in recurrent/refractory DLBCL with 10/11 (90.9%) of evaluable subjects deriving clinical benefit with minimal toxicity. The primary endpoint of this study has been reached with 7/11 (63.6%) of evaluable subjects achieving an objective response warranting further exploration of DPX-Survivac in this population. Enrollment is continuing to further define the patient population most likely to benefit from this well-tolerated therapy. Figure 1 Disclosures Bence-Bruckler: Merck: Membership on an entity's Board of Directors or advisory committees. Forward:Seattle Genetics: Research Funding; IMV: Research Funding; Merck: Research Funding; Astellas: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; IMV: Membership on an entity's Board of Directors or advisory committees; Calgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Stewart:Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Sandoz: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria; Teva: Honoraria. Bramhecha:IMV Inc.: Current Employment. Conlon:IMV Inc.: Current Employment. OffLabel Disclosure: Keytruda (pembrolizumab). Indicated for use in melanoma, nonÃƒÆ'Ã'Â¢ÃƒÂ¢Ã¢â'¬Å¡Ã¢â€šâ'¬ÃƒÂ¢Ã¢â€šâ'¬Ã…â€œsmall cell lung cancer (NSCLC), head and neck squamous cell cancer (HNSCC), classical Hodgkin lymphoma (cHL), primary mediastinal B-cell lymphoma (PMBCL), urothelial carcinoma, microsatellite instability-high (MSI-H) or a mismatch repair deficient (dMMR) solid tumor, gastric or gastroesophageal junction (GEJ) adenocarcinoma, squamous cell carcinoma of the esophagus, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma (MCC), and renal cell carcinoma (RCC).

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Evaluation of cyclophosphamide as an immune enhancer for the NY-ESO-1/ISCOMATRIX vaccine in patients with metastatic melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3093 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3093-3093

Author(s):

Oliver Klein ◽

Ian D. Davis ◽

Grant A. McArthur ◽

Andrew Mark Haydon ◽

Phillip Parente ◽

...

Keyword(s):

Clinical Trial ◽

T Cells ◽

T Cell ◽

Metastatic Melanoma ◽

Cell Response ◽

Low Dose ◽

Advanced Melanoma ◽

T Cell Response ◽

Cd4 T Cell ◽

Vaccine Antigen

3093^ Background: We have previously demonstrated potent immunogenicity of the NY-ESO-1/ISCOMATRIX vaccine in patients with resected melanoma; however the same vaccine induced only a few vaccine antigen specific immune responses in patients with advanced disease. Therefore, we have enrolled a second cohort of patients with advanced melanoma in the clinical trial LUD2002-013 to investigate whether pre-treatment with the immune-modulator cyclophosphamide could improve the immunogenicity of the NY-ESO-1/ISCOMATRIX vaccine. Methods: LUD2002-013 was an open-label phase II study intended to evaluate the safety and immunogenicity of the NY-ESO-1/ISCOMATRIX vaccine in patients with advanced melanoma. The first cohort of patients received vaccine alone; a second cohort with 19 patients was added after evaluation of responses in Cohort 1 and received vaccine in combination with low-dose cyclophosphamide. Patients received 3 injections of NY-ESO-1 ISCOMATRIX preceded, in Cohort 2, by cyclophosphamide at a dose of 300 mg/m2 every four weeks. Assessment of clinical and immunological responses was undertaken at week 11. Results: Fifteen patients of Cohort 2 completed at least one cycle of vaccination. No objective responses were observed with three patients having stable disease for more than three months. The inclusion of cyclophosphamide into the vaccination protocol did not lead to any significant toxicity. Seven of fourteen patients in Cohort 2 developed a vaccine induced NY-ESO-1 specific CD4 T cell response, a significant increase compared to cohort 1 (p=0.019). No differences were observed in the frequency of vaccine induced antibody or CD8 T cell responses. No change in the frequency of peripheral blood regulatory T cells or myeloid derived suppressor cells was detected. Conclusions: The administration of low dose cyclophosphamide has significantly increased the NY-ESO-1 specific CD4 T cell response of the NY-ESO-1/ISCOMATRIX vaccine in patients with metastatic melanoma. Given the emerging importance of CD4 T cells in tumour regression, the present findings warrant further clinical exploration of combining cyclophosphamide with vaccines and other immune-modulatory agents. Clinical trial information: NCT00518206.

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Design and rationale of MASTERKEY-115 phase II trial of talimogene laherparepvec (T-VEC) with pembrolizumab (pembro) in patients with advanced melanoma who progressed on prior anti-programmed cell death-1 (anti-PD-1) therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps10079 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS10079-TPS10079

Author(s):

Jason Alan Chesney ◽

Mohammed M. Milhem ◽

Marya F. Chaney ◽

Priya Gokani ◽

Wendy Snyder ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Objective Response Rate ◽

Cell Activation ◽

Response Rate ◽

Objective Response ◽

Cell Activity ◽

Advanced Melanoma ◽

Durable Response ◽

Metastatic Setting

TPS10079 Background: Treatment options are limited for patients with advanced metastatic or unresectable melanoma, especially after anti-PD-1 failure. T-VEC is an intralesional oncolytic viral immunotherapy designed to selectively replicate in tumor cells and induce local and systemic antitumor response. Pembro promotes T cell activity by blocking PD-1 receptors. Combining T-VEC and pembro may produce robust antitumor activity by increasing T cell activation and blocking T cell inhibition, with a tolerable safety profile. The MASTERKEY-115 trial will evaluate safety and efficacy of T-VEC combined with pembro in patients with advanced melanoma who experienced progressive disease (PD) on prior anti-PD-1 therapy. Methods: NCT04068181 is a phase 2, open-label, single-arm, multicenter trial of T-VEC with pembro in patients with advanced melanoma and PD on prior anti-PD-1. The study is expected to enroll approximately 100 patients and comprises 4 cohorts. Cohorts 1 and 2 will receive anti-PD-1 in a locally recurrent or metastatic setting and experienced PD within 12 weeks of the last anti-PD-1 dose (Cohort 1: PD or stable disease prior to confirmed PD; Cohort 2: complete or partial response prior to confirmed PD). Cohorts 3 and 4 will receive adjuvant anti-PD-1 and were disease-free for < 6 months (Cohort 3) or ≥ 6 months (Cohort 4) prior to confirmed PD. Enrollment criteria include adults with histologically confirmed unresectable or metastatic stage IIIB–IVM1d melanoma, measurable and injectable disease, ECOG PS 0-1, and prior anti-PD-1 (≥ 2-3 consecutive cycles within 8 weeks, immediate prior treatment before enrollment). The primary endpoint is objective response rate per modified RECIST. Key secondary endpoints assess efficacy (objective response rate, best overall response, complete response rate, response duration, durable response rate, disease control rate, progression-free survival, overall survival), safety (incidence of treatment-emergent and treatment-related adverse events, abnormal laboratory tests), and time to subsequent anticancer therapy. The study began enrolling patients in January 2020 and enrollment is ongoing. Clinical trial information: NCT04068181.

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VXM01 phase I study in patients with resectable progression of a glioblastoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.2061 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 2061-2061 ◽

Cited By ~ 2

Author(s):

Wolfgang Wick ◽

Antje Wick ◽

Martha Nowosielski ◽

Felix Sahm ◽

Dennis Riehl ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

Cerebral Blood Volume ◽

Tumor Tissue ◽

Objective Response ◽

Oral Route ◽

Recurrent Glioblastoma ◽

T Cell Response

2061 Background: VXM01 consists of an attenuated Salmonella typhi Ty21a carrying a plasmid encoding for VEGFR-2. The bacterium is serving as a vector via the oral route of administration carrying the plasmid into the Peyer’s plaques. The vaccine construct elicits a systemic T-cell response targeting VEGFR-2. This trial was set up to examine safety and tolerability, clinical and immunogenic response to VXM01 after treatment with at least four vaccinations [106 or 107colony-forming units (CFU)] in patients with recurrent glioblastoma who have failed at least radiochemotherapy with temozolomide. Methods: Patients with progressive resctable glioblastoma were subjected to single oral administration of VXM01 each on day 1, 3, 5, and 7. In addition, VXM01 was allowed to be administered in 4-weekly single doses every 4 weeks during the tumor follow-up period after reoperation. Follow-up was done by weekly safety laboratories and physical examinations in the treatment period and 4-weekly thereafter, MRI including perfusion maps (days 15 and 30 and six-weekly thereafter), 12-weekly T-cell immunomonitoring in the peripheral blood, and brain tumor immunohistochemistry. Results: Eight patients have been treated according to the schedule and surgery has been performed in seven of them. Under VXM01 treatment 47 adverse events, mostly unrelated to VXM01, were observed after a median of 7 doses per patient. Four out of eight patients (50%) showed a VEGFR-2 specific T cell response. In four patients there was a relevant increase in cerebral blood volume and apparent diffusion coefficient on post-vaccination MRI. In one patient there was an objective and durable T1 response, whereas three further patients remained stable prior to surgery and thereafter. Evaluation of infiltrating T cells in the tissue from re-operation revealed an increase in CD8+ T-cells in 5 out of 7 patients relative to the primary tumor tissue. Conclusions: VXM01 was safe and produces specific peripheral immune responses as well as enumeration of tumor-infiltrating T-cells in post-vaccine tumor tissue. Post treatment MRI imply vascular normalization and there was one patient with an objective response. As a consequence of this data, an expansion cohort of this trial has been launched. Clinical trial information: NCT02718443.

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