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BackgroundThe tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is an autologous tumor vaccine that decreased recurrence in stage III/IV melanoma when granulocyte-colony stimulating factor (G-CSF) was not used to harvest the dendritic cells in a randomized phase 2B adjuvant trial.1The tumor lysate (TL) particle only (TLPO) vaccine utilizes a similar mechanism, but with autologous TL-loaded yeast cell wall particles; this eliminates the need for dendritic cell (DC) collection and ex-vivo loading and reduces production costs and time. The TLPO vaccine was compared to TLPLDC in an embedded bridging portion of the trial. Here, we examine 36-month outcomes of the ongoing randomized, double-blind phase 2 trial in patients (pts) with resected stage III/IV melanoma.MethodsPts were randomized 2:1 to receive TLPO or TLPLDC as a continuation of a previously established clinical trial comparing TLPLDC versus placebo. The TLPLDC group was analyzed separately based on use (or not) of G-CSF for collection of DC. Safety was measured by the Common Terminology Criteria for Adverse Events (CTCAE). Kaplan-Meier and log-rank analysis was used to compare 36-month disease-free survival (DFS) and overall survival (OS) in the intention-to-treat (ITT) main arms as well as pre-specified subgroups.ResultsA total of 187 pts were randomized with 41, 47, 56, and 43 pts enrolled in the placebo, TLPLDC without G-CSF (TLPLDC), TLPLDC with G-CSF (TLPLDC+G), and TLPO arm, respectively. Pts randomized to the TLPO arm were more likely to have stage IV melanoma (22.0% for placebo, 20.4% for TLPLDC and TLPLDC+G, and 44.2% for TLPO; p = 0.002) and to receive prior immunotherapy (36.6% for placebo, 39.8% for both TLPLDC and TLPLDC+G, and 83.7% for TLPO; p < 0.001). Grade 3+ adverse events were not significantly different between arms. In the ITT analysis, 36-month DFS was 30.0% for placebo, 55.8% for TLPLDC, 24.4% for TLPLDC+G, and 64.0% for TLPO (p < 0.001). OS at 36 months was 70.9% for placebo, 94.2% for TLPLDC, 69.8%% for TLPLDC+G, and 94.8% for TLPO (p = 0.011) (figure 1).Abstract 542 Figure 1Kaplan-Meier curves demonstrating DFS (A) and OS (B) between Placebo (n=41), TLPLDC (n=47), TLPLDC+G (n=56), and TLPO (n=43)ConclusionsThe TLPO and TLPLDC (without G-CSF) vaccines improved 36-month DFS and OS in this randomized phase 2 trial. The efficacy of the TLPO and TLPLDC vaccines will be confirmed in a phase III trial in resected Stage III/IV melanoma pts.Trial RegistrationNIH, clinicaltrials.gov, NCT02301611ReferencesO’Shea AE, Chick RC, Clifton GT, et al. The effect of pretreatment with G-CSF prior to dendritic cell collection during the phase IIb trial of an autologous DC-based vaccine for advanced, resectable melanoma. Presented at: Society for Immunotherapy of Cancer 35th Anniversary Annual Meeting & Preconference Programs (SITC 2020); November 11–14, 2020. Abstract 310. J Immunother Cancer. 2020;8(Suppl 3):A656–A959.Ethics ApprovalThe clinical trial protocol was approved by the Western Institutional Review Board (2014–1932). All participants provided informed consent prior to enrollment in the trial.

Background We have completed a prospective, randomized, multi-center, double-blind, placebo-controlled phase IIb trial of the tumor lysate, particle loaded, dendritic cell (TLPLDC) vaccine given to prevent recurrences in patients with resected stage III/IV melanoma. During the trial, granulocyte colony stimulating factor (G-CSF) was administered to some patients to mobilize dendritic cells (DCs) precursors prior to harvest, allowing for similar DC yield with reduced blood draws. This study examines the impact of DC collection methods on vaccine effectiveness. Methods TLPLDC is produced by loading tumor lysate into pre-prepared yeast cell wall particles (YCWPs) and exposing them to autologous DCs. DC precursors were isolated either by collection of 50–70 mL of blood following pre-administration of 300µg of G-CSF 24–48 hrs prior, or collection of 120 mL of peripheral blood without G-CSF pretreatment based on patient and provider preference. Patients were randomized 2:1 to receive TLPLDC or placebo (DCs exposed to empty YCWPs). 1–1.5 × 106 cells/dose were injected intradermally at 0, 1, 2, 6, 12, and 18 months. Differences in disease free survival (DFS) and overall survival (OS) were analyzed by log rank. Results Of 144 patients randomized, 103 received TLPLDC and 41 received placebo. Within the TLPLDC group, 57 received pretreatment with G-CSF (TLPLDC+G-CSF) and 46 did not (TLPLDC–G-CSF). There were no significant clinicopathologic or treatment differences between the three treatment arms. 36-month DFS was significantly better in TLPLDC–G-CSF vs. TLPLDC+G-CSF or placebo (51.8% vs. 23.4% and 27.1% respectively, p=0.027) (figure 1). TLPLDC–G-CSF had correspondingly improved OS (92.9% vs. 62.8% and 72.3% respectively, p=0.022) (figure 2). Subgroup analysis revealed TLPLDC–G-CSF had increased DFS over TLPLDC+G-CSF or placebo in Stage IV (68.6% vs. 18.8% and 0.0% respectively, p=0.058). Similarly, the DFS survival benefit of TLPLDC–G-CSF was enhanced in patients who received prior immunotherapy (IO) (61.9% vs. 11.5% and 35.7% respectively, p=0.007) or checkpoint inhibitors (CPI) (48.5% vs. 10.6% and 37.5% respectively, p=0.039). Conclusions TLPLDC vaccine created without G-CSF pretreatment significantly improved 36-month DFS and OS compared to TLPLDC+G-CSF or placebo in stage III/IV (resected) melanoma patients. On further subgroup analysis, the increases in OS and DFS were more profound in patients who received additional immune therapies to include CPI. Ongoing evaluation will determine if G-CSF mobilization leads to collection of phenotypically different DCs. Based on these results, we are planning a phase III trial of TLPLDC–G-CSF + CPI vs. placebo + CPI in advanced melanoma post-resection. Trial Registration ClinicalTrials. gov Identifier: NCT02301611 Ethics Approval This study was reviewed and approved by the IRB or Independent Ethics Committee (IEC) of each participating center prior to study initiation.

Background The autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is safe and effective in improving 24 and 36-month disease-free survival (DFS) in patients (pts) with resected stage III/IV melanoma who completed the primary vaccine series. The tumor lysate, particle only (TLPO) vaccine has been developed to accelerate production by omitting DC isolation and ex vivo loading in favor of in vivo phagocytosis of the TL-loaded particles. We are currently conducting a randomized and double-blind trial of the TLPO vs TLPLDC to improve DFS and overall survival (OS) in patients with resected late stage melanoma. Methods Patients with stage III/IV melanoma who were clinically disease-free after standard of care therapies were randomized to receive TLPO vs TLPLDC (2:1) as a continuation of the phase IIb trial comparing TLPLDC vs placebo (2:1). For the TLPLDC vaccine, autologous TL was loaded into yeast cell wall particles (YCWP) which were then phagocytized by isolated autologous DC ex vivo. For the placebo DC were loaded with empty YCWP. For TLPO, the autologous TL-loaded YCWP were coated with a chemoattractant and injected intradermally for in vivo phagocytosis. Some patients in the TLPLDC arm received G-CSF prior to DC harvest to minimize blood draw (60 mL instead of 120 mL without G-CSF). For all arms, six vaccine/placebo doses were administered intradermally at 0, 1, 2, 6, 12, and 18 mos. Data was analyzed by an intention-to-treat (ITT) analysis for DFS and OS by the Kaplan-Meier method and compared by log-rank test. Results 63 pts were randomized to TLPO (n=43) vs TLPLDC (n=20). The TLPO cohort contained more females and received less chemotherapy (0% vs 10%), but otherwise were comparable. There were no differences in DFS (p=0.948) or OS (p=0.779) between the two vaccines (figures 1&2). Comparing the TLPO pts to all other pts in the phase IIb trial [TLPLDC+G-CSF (n=57), TLPLDC-G-CSF (n=46), and placebo (n=41)] the TLPO arm had improved DFS compared to placebo (p=0.019) and TLPLDC+G-CSF (p=0.001), but roughly equivalent to the TLPLDC-G-CSF arm (p=0.276) (figure 3). A similar trend was seen in OS analysis, though differences were not statistically significant (figure 4). Conclusions TLPO and TLPLDC vaccines (without the use of G-CSF) improve DFS in patients with resected stage III/IV melanoma compared to placebo. The TLPO vaccine may offer advantages via reduced cost and vaccine production time. TLPO should be closely considered for further clinical trials. Trial Registration NCT02301611: Phase IIB TL + YWCP + DC in MelanomaTLPLDC IND#16101TLPO IND#17274 Ethics Approval This study was approved by WIRB; protocol #20141932

Background The tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is created ex vivo by loading autologous dendritic cells (DC) with yeast cell wall particles (YCWP) containing autologous tumor lysate, thus delivering tumor antigens to the DC cytoplasm via phagocytosis. TLPLDC then activates a robust T cell response against the unique antigens for each patient. The primary analysis of the prospective, randomized, multi-center, double-blind, placebo-controlled phase IIb trial in patients with resected stage III/IV melanoma showed TLPLDC improved 24-month disease-free survival (DFS) in the per-treatment (PT) analysis (patients completing the 6-month primary vaccine series). Here, we examine the secondary endpoint of 36-month DFS and overall survival (OS). Methods Patients with resected stage III/IV melanoma were randomized 2:1 to TLPLDC vaccine or placebo (autologous DC loaded with empty YCWP). Treatments were given at 0, 1, 2, 6, 12 and 18 months. The protocol was amended to include patients receiving concurrent checkpoint inhibitors (CPIs) to follow changes in standard of care. The co-primary endpoints were 24-month DFS by intention-to-treat (IT) analysis and per-treatment (PT) analysis, with secondary endpoints including 36-month DFS and OS by ITT and PT analysis, pre-specified analysis by stage, and safety as measured by CTCAE v4.03. Results Overall, 103 patients received TLPLDC and 41 placebo. In PT analysis, 65 patients received TLPLDC and 32 placebo. Total adverse events (AEs), grade 3+ AEs, and serious AEs (SAEs) were similar in placebo vs TLPLDC groups, with one related SAE per treatment arm. By ITT analysis, 36-month OS was 76.2% for TLPLDC vs 70.3% for placebo (HR 0.72, p=0.437) and 36-month DFS was 35.6% vs 27.1% (HR 0.95, p=0.841). By PT analysis, 36-month DFS was improved with TLPLDC (57.5% vs 35.0%; HR 0.50, p=0.025, figure 1). This effect was even more dramatic in resected stage IV patients (36-month DFS: 60.9% vs 0%; HR 0.12, p=0.001, figure 2). Conclusions This phase IIb trial again demonstrates the safety of the TLPLDC vaccine, and an improved 36-month DFS in patients with resected stage III/IV melanoma who complete the primary vaccine series, particularly in the stage IV subgroup. Next, a phase III trial will evaluate the efficacy of TLPLDC vaccine as adjuvant treatment for resected stage IV melanoma, with patients randomized to receive standard of care PD-1 inhibitors + TLPLDC versus PD-1 inhibitors + placebo. Trial Registration This is a phase IIb clinical trial registered under NCT02301611 Ethics Approval This study was approved by Western IRB, protocol 20141932.