Tumor Lysate Particle Only Vaccine (TLPO) vs. Tumor Lysate Particle-Loaded, Dendritic Cell Vaccine (TLPLDC) to Prevent Recurrence in Resected Stage III/IV Melanoma Patients: Results of a Phase I/IIa Trial

doi:10.21203/rs.3.rs-4088449/v1

Background:

The autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is produced from dendritic cells (DC) loaded ex vivo with autologous tumor lysate (TL). TLPLDC has been shown to decrease recurrence in resected Stage III/IV melanoma patients in a Phase IIb trial. The TL particle only (TLPO) vaccine is produced by loading of yeast cell wall particles with autologous TL and direct injection allowing for in vivo DC loading. We have compared the TLPO and TLPLDC vaccines in an embedded Phase I/IIa trial of a larger Phase IIb trial of the TLPLDC vaccine.

Methods:

Patients rendered clinically disease-free after surgery were randomized 2:1 to receive the TLPO or TLPLDC vaccine and followed for recurrence and death. Patients had scheduled intradermal inoculations at 0, 1, 2, 6, 12, and 18 months after enrollment. Kaplan-Meier and log-rank analysis were used to compare disease-free survival (DFS) and overall survival (OS) in an intention-to-treat (ITT) analysis.

Results:

Sixty-three patients were randomized, 43 TLPO and 20 TLPLDC. Patients randomized to the TLPO arm were more likely to be female (37.2% vs. 10.0%, p = 0.026), but otherwise no significant clinicopathological differences were identified. No differences in related adverse events (AE) were found between treatment arms. At a median follow-up of 20.5 months, the DFS (60.8% vs. 58.7%, p = 0.714) and OS (94.6% vs. 93.8%, p = 0.966) were equivalent between the TLPO and TLPLDC groups, respectively. No statistical differences were found in subgroup analyses between vaccine types, which accounted for receipt of immunotherapy and the use of G-CSF pre-blood draw.

Conclusions:

In a randomized, double-blind Phase I/IIa trial, there were no differences in DFS or OS in resected Stage III/IV melanoma patients receiving adjuvant TLPO versus TLPLDC vaccines. Given manufacturing advantages, further efficacy testing of TLPO is warranted in a Phase III trial.

Trial Registration

This is a clinical trial registered under NCT02301611.

Cancer vaccine

melanoma

dendritic cell

immunotherapy

personalized medicine

While melanoma is the third most common skin cancer, it is the most lethal of the cutaneous malignancies¹. Early-stage disease is frequently cured via surgical resection, however patients with advanced disease are at high risk of recurrence. Amongst patients with recurrence, up to 70% will die from their disease within 5 years.^{2, 3} Immunotherapy has shown significant promise in advanced melanoma, particularly with the advent of immune checkpoint inhibitors (CPIs).^{2, 4–7} While these therapies are beneficial in some patients, risk of toxicity does limit their use.⁷ Additionally, these therapies are non-specific, and many patients with melanoma do not respond (primary or acquired resistance), at least in part due to a lack of a pre-existing immune response to their tumor.^7,8 Newer investigative therapies aimed at generating a tumor-specific immunological response with a low toxicity profile include oncolytic viruses and cancer vaccines.^9,10

The tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine has been previously described by our research group and tested in both the adjuvant as well as the metastatic setting in combination with other systemic therapies. Vaccine production involves loading autologous monocytic-derived dendritic cells (DCs) ex vivo with immune-stimulating yeast cell wall particles (YCWP) that contain autologous tumor lysate (TL), creating a personalized vaccine that has had encouraging results in the primary analysis of a Phase IIb trial.^{11, 12} The preparation strategy of the TLPLDC vaccine is complex, however, requiring a 120mL blood draw for DC harvest, isolation, preparation, and ex-vivo phagocytosis of TL-loaded YCWP, followed by intradermal injection of DCs into the patient. In an effort to draw less peripheral blood to isolate sufficient monocytes for DC maturation in, we offered as an option a single injection of G-CSF to elevate the white blood cell count and reduce by 50% the blood volume drawn at 24–48 hrs. Production and quality assurance (QA) testing lasts approximately three weeks and is costly. A novel iteration of this vaccine concept, a tumor lysate, particle-only (TLPO) vaccine, involves TL-loaded YCWPs capped with silicate for content retention and attraction of a monocytic infiltrate. This formulation can then be directly inoculated, allowing DCs to uptake the TL-loaded YCWP in vivo, circumventing multiple steps of TLPLDC production.¹³

The TLPO vaccine was studied in an embedded, randomized Phase I/IIa trial of a larger Phase IIb trial of the TLPLDC vaccine. Here, we report the final outcomes of this trial comparing patients randomized to receiving the TLPO vaccine to those receiving the TLPLDC vaccine. The primary outcome for this study was an assessment of safety, while secondary outcomes included disease-free survival (DFS) and overall survival (OS). Subgroup analyses examined differences in disease characteristics and treatments including CPI therapy.

Patients

The protocol was approved by the Western Institutional Review Board (IRB) and site IRBs. Patients 18 years of age or older with Stage III or IV melanoma capable of being rendered clinically disease-free after surgery were recruited at individual study sites. Additional inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 and the ability to provide approximately 1cm³ (or 1mg minimum) of tumor for vaccine production. A further requirement was completion of standard adjuvant therapy per National Comprehensive Cancer Network (NCCN) guidelines. The protocol was amended during the trial to allow enrollment of patients on CPI therapy to participate in this study given the change to standard treatment of melanoma. Patients receiving CPI therapy were permitted to enroll if they had tolerated this therapy for 3 months before randomization. Patients were excluded if they had evidence of residual disease after surgery and adjuvant treatment, were unable to provide sufficient tumor for vaccine production, or were immunosuppressed. Patients were consented twice: once prior to surgery during the process of tissue collection and again after completion of standard of care (SoC) treatment before vaccination.

Patient randomization

Starting February 2015, patients enrolled in the aforementioned Phase IIB TLPLDC trial were randomized in a 2:1 allocation ratio to either the TLPLDC vaccine or placebo by the clinical research organization (CRO), using a computer-generated randomization scheme and a site-balancing algorithm. After the 120th patient was randomized to TLPLDC or placebo, the TLPO Phase I/IIa embedded trial commenced with a 2:1 randomization for a total of 63 patients between the TLPO versus the TLPLDC vaccine. This report focuses on the results of the Phase I/IIa portion of the trial. Patients, treating physicians, study personnel including site principal investigators (PIs), and clinical and medical monitors were blinded to the treatment groups.

Safety Monitoring and Follow-up

Patients were monitored after inoculation for thirty minutes for both primary and booster vaccination, with vital signs taken as needed. Local or systemic toxicities were assessed, collected, and graded by the research staff at the patient’s next visit. Reporting of adverse events (AE) was performed in accordance with a Data Safety Monitoring Plan and categorized according to the National Cancer Institute (NCI) Common Terminology Criteria of Adverse Events (CTCAE) v4.03 toxicity scale. AEs were defined as any negative medical occurrence in a study participant during the trial, regardless of causality. Treatment-related AEs were classified as “definitely,” probably,” or “possibly” related by the study site principal investigator (PI). Serious AEs (SAEs) were defined as any AE occurring at any dose which resulted in death, a life-threatening event, inpatient hospitalization, congenital anomaly/birth defect, disability, or required medical or surgical intervention to prevent a listed outcome.

All patients were followed for recurrence with a history and physical exam every 3–6 months, with laboratory and radiographic surveillance as determined by their treating physician. If a patient recurred in either treatment arm, they were offered participation in the open label portion of the study with TLPLDC vaccination along with SoC therapy.¹⁴ All enrolled patients, regardless of randomization, were followed for clinical recurrence and survival for a minimum of three years. Open label patients were followed for an additional one year. Protocol-specific therapy was discontinued for progressive disease (PD), unacceptable toxicity as measured by the National Cancer Institute CTCAE v4.03 toxicity scale, patient preference, or physician judgement.

Vaccine production

Tumor tissue collection was performed at the time of surgical resection or pre-treatment biopsy. Vaccines were produced by Orbis Health Solutions (Greenville, SC).

For production of the TLPO vaccine, YCWP are first created from Saccharomyces cerevisiae by NaOH/HCl digestion of all non-cell wall components and then washed, producing β-glycan shells. These are then loaded with autologous TL created by freeze/thaw cycling of ≥ 1mg collected tumor, as well as CpG oligonucleotides and a tetanus helper peptide. These TL-loaded YCWP are aliquoted and cryopreserved after being capped with silicate to seal in the TL content and attract a monocytic infiltrate.¹³

The TLPLDC vaccine production has been previously described but will briefly be reviewed.^11,14 After standard treatment is completed and based on provider and patient preference, the patient either had a subcutaneous injection of 300µg of granulocyte-colony stimulating factor (G-CSF) followed by a 70mL blood draw collection 24-48hr later, or the patient had a single 120mL blood draw. DC isolation and preparation was performed at a centralized lab. TL from the patient’s tumor were loaded into YCWP, and then used to load DC cells ex vivo.

The full vaccination course (six doses) of TLPDC or TLPO vaccine was produced after randomization. The inoculation series was started between three weeks and three months after completion of standard treatment. The primary vaccine series (PVS), comprised of doses administered at 0, 1, and 2 months, was followed by vaccine boosters administered at 6, 12, and 18 months. Tumor samples were maintained for all patients for reproduction of vaccine in the case of disease recurrence.

Analysis Plan

For the TLPO Phase I/IIa portion of this trial, the primary endpoint was safety of the vaccine. Total, related, and serious AEs were examined between the TLPO and TLPLDC vaccination arms. Secondary endpoints included 36-month DFS and OS. Exploratory subgroups included patients who received CPIs and those who received G-CSF prior to their blood draw.

Statistics were calculated using SPSS (version 22, IBM Corp, Released 2013, Armonk, NY). Demographic data was analyzed using either Student’s t-test or Mann-Whitney U-test for continuous variables and Chi-square regression for categorical variables. Median follow-up was calculated by excluding any patient who died prior to 36 months. Kaplan-Meier (KM) and log-rank analysis were used to estimate and compare DFS and OS in an intention-to-treat (ITT) analysis. Cox proportional hazards modeling was performed to determine the impact on survival of pre-specified factors including pre-treatment with G-CSF prior to blood draw and other exploratory factors such as receipt of immunotherapy. AEs were examined between groups using Pearson’s chi-square test. A p-value < 0.05 was considered significant for all analyses.

Demographics

A total of 63 patients were randomized in a 2:1 allocation to receive either the TLPO (n = 43) or TLPLDC vaccine (n = 20) (Fig. 1). Patients in the TLPO vaccination arm were more likely to be female than in the TLPLDC arm (37.2% vs. 10.0%, p = 0.026), but otherwise no significant clinicopathological (Table 1A) or treatment (Table 1B) differences were identified between the two groups.

Primary Safety Endpoints

A total of 40/63 patients (63.5%) experienced any (related and unrelated) AE, with 186 cumulative AEs (111 TLPO, 75 TLPLDC, p = 0.21). Of these, 20/63 patients (31.7%) experienced any related AE, for a total of 70 related AEs (38 TLPO, 32 TLPLDC, p = 0.57). Of these related AEs, 92.9% were classified as Grade 1 and 7.1% as Grade 2. There were no patients who experienced a related AE ≥ Grade 3. Most frequent related AEs (occurring in > 5% of patients) included local reactions to vaccine administration [injection site reactions, skin induration (58.6%)], pruritis (5.7%), and fatigue (5.7%). There was a significant difference between the rate of local reactions to vaccine administration among related AE between groups, TLPO 47.4%, TLPLDC 71.9% (p = 0.038). A total of 16 SAEs occurred in the study among 10 patients (11 TLPO, 5 TLPLDC, p = 0.44). The most frequent SAEs were infections. Only one patient (TLPO vaccination arm) had a related SAE, a pleural effusion requiring an eight-day hospitalization.

Secondary Survival Endpoints

At the time of the analysis, median follow-up was 20.5 months. By ITT analysis, there was no difference in 36-month DFS or OS between the TLPO or TLPLDC vaccination arms (Fig. 2). Cumulative DFS was 60.8% for the TLPO group and 58.7% for the TLPLDC group (p = 0.714). Cumulative OS was 94.6% for the TLPO group and 93.8% for the TLPLDC group (p = 0.966).

Subgroup Analyses

CPI therapy between groups was not stratified during randomization. When limiting analysis to patients who received CPI therapy, there was no significant difference in DFS between TLPO and TLPLDC (p = .802) (Fig. 3).

Pre-treatment of G-CSF to reduce the volume of blood draw required was not randomized. By ITT, there was no difference in 36-month DFS between TLPO versus TLPLDC without pre-treatment of G-CSF (p = .131) or TLPO versus TLPLDC with pre-treatment of G-CSF (p = .263) (Fig. 4).

In Cox proportional-hazards modeling, no statistically significant impact on disease free survival was observed within various sub-groups: receipt of immunotherapy, CPI therapy, pre-treatment with G-CSF, stage III disease, or recurrent disease.

In this prospective, randomized, double-blind embedded Phase I/IIa trial of clinically disease-free patients with high-risk melanoma, the TLPO and TLPLDC vaccines were well-tolerated and safe, with no significant difference in adverse events between the two trial arms. Additionally, at a median follow-up 20.5 months, DFS and OS were equivalent between the TLPO and TLPLDC vaccines.

There are many approaches to cancer vaccination. Most past cancer vaccine development has targeted tumor-associated antigens (TAAs) that are common among cancers with little or no expression on healthy tissues. However, these “off-the-shelf” vaccines are often limited to patients who express the targeted antigen(s), generate an immune response towards a small number of antigens, and may not target the most antigenic epitopes for a specific individual.^{13, 15, 16} Personalized vaccines are an attractive alternative to overcome these potential shortcomings. Personalized vaccines target neoantigens that arise from unique cancer-specific mutations and may be more immunogenic than aberrantly expressed TAAs. However, neoantigen-targeting personalized vaccines require tumor tissue for production and have increased processing and production costs.¹⁶

Vaccines utilizing a DC-based approach to activate the immune system have had some success. The only FDA-approved DC-based cancer vaccine, an autologous cellular immunological agent, sipuleucel-T (Provenge ®), targets metastatic castration-resistant (hormone refractory) prostate cancer and uses a similar DC delivery mechanism to the TLPLDC vaccine, though targeting prostatic-acid phosphatase (PAP) instead of utilizing tumor lysate.¹⁷ However, while this vaccine carries modest survival benefit (median OS of 25.8 versus 21.7 months for placebo), both cost and complexity of production of personalized neoantigen cancer vaccines have hindered widespread use.¹⁶ Combining the benefits of a DC-based vaccine that targets neoantigens, while minimizing production costs through use of in-vivo neoantigen processing, may be a superior approach.

As previously discussed, the TLPLDC vaccine has the advantage of using autologous TL, personalizing it to each patient. However, the TLPLDC vaccine requires harvest, isolation, and preparation of DC cells, followed by ex vivo loading of DC with autologous antigen, like sipuleucel-T. The TLPO vaccine is alike in that it presents autologous antigen, but this vaccine is instead created from TL-loaded YCWP capped with silicate and inoculated for presentation to DCs for in vivo loading. Thus, it offers the benefits of a personalized cancer vaccine like TLPLDC, but with significant advantages from a manufacturing standpoint.¹⁸ Furthermore, the acellular nature of the TLPO vaccine translates to significant other benefits over the TLPLDC vaccine including improved handling, delivery, and shelf-stability.

There were initial challenges in TLPO production that had to be overcome. Our group developed the concept of utilizing YCWP as an efficient and effective means of loading dendritic cells in vivo without the need for ex vivo processing of DCs.^{16, 18} In the initial development of the TLPO vaccine, however, the TL escaped the YCWP when given as an inoculation, which had not been encountered with the previous technique of loading DCs ex vivo. A silicate cap for the YCWP was developed with a thickness of 0.0615 +/- 0.0009-micron (approximately 140 molecular layers), which allows the YCWP to contain the TL until the time of phagocytosis by DCs. Preclinical work done to assess the effectiveness of this “capping” of the YCWP evaluated the mean TL protein content by measuring nitrogen content via combustion analysis. With the addition of silicate cap, TL was sufficiently retained within the YCWP. This innovation led to the TLPO vaccine formulation that is currently being studied.¹⁹

With this barrier surpassed, this study represents the first trial of the TLPO vaccine in humans. The TLPLDC vaccine has been previously demonstrated to be safe both alone and in combination with standard therapies.^12,14 Here, we demonstrate no differences in total, related, or serious AEs between the two trial arms (TLPO versus TLPLDC vaccines), and moreover no related grade 3 or greater toxicities in either arm. TLPLDC demonstrates greater local administration site reactions, presumably due to the immunogenic nature of the TLPLDC ex vivo dendritic cell processing versus the acellular TLPO. Despite this greater immunogenicity demonstrated at the injection site, similar vaccine efficacy is observed between TLPO and TLPLDC.

While the primary outcome of this study was a safety assessment, secondary outcomes included an assessment of efficacy. The overall results of this trial demonstrate equivalence in outcomes between the TLPO and TLPLDC vaccines. In a previously published per-treatment primary (PT) analysis of a Phase IIb trial comparing the TLPLDC vaccine to placebo, there was improved 24-month DFS in the vaccine group (62.9% vs. 34.8%, p = 0.041).¹² Additionally, a larger analysis of a placebo-controlled, four-arm trial including TLPLDC with and without G-CSF, TLPO and Placebo demonstrated the promising efficacy of TLPLDC and TLPO.²²

These results, while preliminary, are encouraging given published findings in other Phase II trials of personalized vaccines in the adjuvant setting in high-risk melanoma. Khattak et al describe the use of a personalized mRNA vaccine encoding up to 34 of a patient’s tumor neoantigens to treat stage III and IV cutaneous melanoma.²¹ They report an improvement in recurrence free survival when the mRNA vaccine is given concomitantly with CPI therapy versus CPI therapy alone.

Here we demonstrate similar outcomes of TLPO to the TLPLDC vaccine with or without G-CSF, suggesting that the TLPO vaccine could be developed at substantially reduced costs and production time while maintaining therapeutic safety and efficacy. In addition to the overall results, subgroup analyses demonstrate no statistically significant impact on survival from choice of vaccine across various subgroups: those who received other forms of immunotherapy, those who received CPIs specifically, or those pre-treated with G-CSF. Our group previously investigated the DC gene expression via RNA-sequencing analysis and found patients who used G-CSF to reduce blood draw volume had many immature DC and the expedited maturation process was not sufficient.²⁰ Based on findings from this embedded Phase I/IIa trial in combination with results of the larger Phase IIb placebo-controlled, four-arm vaccine trial²², future studies will proceed comparing the TLPO vaccine to placebo in combination with other standard therapies, given the clear manufacturing and production advantage of the TLPO over TLPLDC vaccine.

There were several limitations to this study. The primary outcome being examined in this study was safety. As an embedded study with a small sample size, the power of any efficacy analysis is severely limited and hypothesis-generating only. Further trials will look to corroborate these results with a more robust sample size. Similarly, several subgroup analyses were exploratory in nature and therefore no definitive conclusions can be drawn, though they are useful in developing later studies. Finally, immunotherapy and G-CSF were not randomized, but rather given at the discretion of the patient and treating physician. The protocol was amended to permit CPI therapy once approved for use in the adjuvant setting.

We present results from an embedded Phase I/IIa trial of a larger Phase IIb trial of the TLPLDC vaccine, demonstrating the safety of the well-tolerated TLPO vaccine and secondarily equivalent DFS and OS when compared to the TLPLDC vaccine. A Phase III trial is planned to compare the TLPO vaccine to placebo in combination with current standard regimens.

Abbreviation	Definition
AE	Adverse Event
CPI	Checkpoint Inhibitor
CRO	Clinical Research Organization
CTCAE	Common Terminology Criteria of Adverse Events
DC	Dendritic Cell
DFS	Disease Free Survival
ECOG	Eastern Cooperative Oncology Group
G-CSP	Granulocyte-Colony Stimulating Factor
IRB	Institutional Review Board
ITT	Intent-To-Treat
KM	Kaplan-Meier
NCCN	National Comprehensive Cancer Network
NCI	National Cancer Institute
OS	Overall Survival
PI	Principal Investigator
PD	Progressive Disease
PT	Per-treatment primary
PVS	Primary Vaccine Series
SAE	Serious Adverse Event
TAA	Tumor Associated Antigen
TL	Tumor Lysate
TLPLDC	Tumor Lysate, Particle-Loaded, Dendritic Cel Vaccine
TLPLDC+G	Tumor Lysate, Particle-Loaded, Dendritic Cel Vaccine with G-CSF
TLPO	Tumor Lysate, Particle Only Vaccine
YCWP	Yeast Cell Wall Particles

Trial Registration: This is a clinical trial registered under NCT02301611.

https://clinicaltrials.gov/study/NCT02301611?term=NCT02301611&rank=1

Ethics Approval: This trial was approved by Western IRB, protocol 20141932.

Funding: This study was sponsored by Elios Therapeutics, LLC, Greenville, SC.

The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the US Army Medical Department, the Department of the Army, Department of the Air Force, Department of Defense, or the US Government. The voluntary, fully informed consent of the subjects used in this research was obtained as required by 32 CFR 219 and DODI 3216.02_AFI40-402.

Ethical Approval

The protocol was approved by the Western Institutional Review Board and all patients provided informed consent for participation.

Consent to Participate Declaration: Allpatients provided informed consent twice: once prior to surgery during the process of tissue collection and again after completion of standard of care (SoC) treatment before vaccination.

Competing interests

Dr. Faries is an advisor for Bristol-Myers Squibb, Sanofi, Array Bioscience and Pulse Bioscience. Dr. Wagner is an employee of Orbis Health Solutions. Dr. Peoples is employed by Orbis Health Solutions and Cancer Insight; is a consultant for Rapamycin Holdings, Heat Biologics, Abexxa Biologics, and Pelican Therapeutics; and has received funding from the above as well as Sellas Life Sciences and Genentech. Dr Jakub served on a Novartis Melanoma Surgical Oncology Advisory Board. Dr. Clifton is employed by Parthenon Therapeutics. All remaining authors have declared no conflicts of interest.

Authors' contributions

All authors listed (SV, EC, AM, RC, GT, AS, TV, FV, AT, AO, PM, DH, PK, AH, JC, JH, AB, JJ, JS, MS, XY, TW, MF, GP) provided substantial contributions to the conception and production of this manuscript including data analysis, drafting and editing. All authors agree to the accountability and integrity of this work. Final approval held by GP.

Funding

The study was sponsored and funded by Elios Therapeutics, LLC, Greenville, SC.

Availability of data and materials

The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are located in controlled access data storage.

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Table 1

A. Demographic and Pathologic Data for TLPLDC (n = 20) versus TLPO (n = 43) vaccination arms.
Category		Randomization Arms				P-Value
		TLPLDC Vaccine		TLPO Vaccine
		Count	Count %	Count	Count %
Age	Median (range)	60.3 (34.1–86.3)		63.6 (37.3–83.6)		0.83
Sex	Female	2	10.0%	16	37.2%	0.03
Sex	Male	18	90.0%	27	62.8%	0.03
Race	Black	0	0.0%	1	2.3%	0.38
	Hispanic	1	5.0%	0	0.0%
	White	19	95.0%	41	95.3%
	White, Hispanic	0	0.0%	1	2.3%
	Asian	0	0.0%	0	0.0%
	Native American	0	0.0%	0	0.0%
Breslow (mm)	Median (range)	2 (0–14)		3 (1–15)		0.16
Ulceration	Missing	13	65.0%	25	58.1%	0.46
	Absent	3	15.0%	13	30.2%
	Present	4	20.0%	5	11.6%
Mitotic Rate	Missing	6	30.0%	12	27.9%	0.25
	≥1	6	30.0%	16	37.2%
	0	4	20.0%	2	4.7%
	NA	4	20.0%	13	30.2%
Staging	Primary	6	30.0%	10	23.3%	0.57
Staging	Recurrent	14	70.0%	33	76.7%	0.57
Stage III vs. IV	III	16	80.0%	24	55.8%	0.06
Stage III vs. IV	IV	4	20.0%	19	44.2%	0.06
T Stage	Missing	1	5.0%	5	11.6%	0.07
	T1	4	20.0%	3	7.0%
	T2	6	30.0%	3	7.0%
	T3	3	15.0%	10	23.3%
	T4	3	15.0%	15	34.9%
	TX	3	15.0%	7	16.3%
N Stage	Missing	3	15.0%	13	30.2%	0.36
	N1	8	40.0%	12	27.9%
	N2	2	10.0%	8	18.6%
	N3	7	35.0%	10	23.3%
M Stage	M0	16	80.0%	24	55.8%	0.23
	M1a	1	5.0%	11	25.6%
	M1b	1	5.0%	4	9.3%
	M1c	2	10.0%	3	7.0%
	MX	0	0.0%	1	2.3%

Table 1

B. Treatment Data for TLPLDC (n = 20) versus TLPO (n = 43) vaccination arms.
Category		Randomization Arms				P-Value
		TLPLDC Vaccine		TLPO Vaccine
		Count	Count %	Count	Count %
Immunotherapy	No	6	30.0%	7	16.3%	0.21
Immunotherapy	Yes	14	70.0%	36	83.7%	0.21
CPI	No	6	30.0%	8	18.6%	0.31
CPI	Yes	14	70.0%	35	81.4%	0.31
Interferon Alpha (INF-alpha)	Missing	12	60.0%	23	53.5%	0.71
	No	7	35.0%	19	44.2%
	Yes	1	5.0%	1	2.3%
Interleukin (IL-2)	Missing	12	60.0%	23	53.5%	0.26
	No	7	35.0%	20	46.5%
	Yes	1	5.0%	0	0.0%
BRAF Inhibitor	No	17	85.0%	38	88.4%	0.71
BRAF Inhibitor	Yes	3	15.0%	5	11.6%	0.71
Radiation	No	15	75.0%	33	76.7%	0.88
Radiation	Yes	5	25.0%	10	23.3%	0.88
G-CSF	No	11	55.0%	21	48.8%	0.65
G-CSF	Yes	9	45.0%	22	51.2%	0.65

Competing interest reported. Dr. Faries is an advisor for Bristol-Myers Squibb, Sanofi, Array Bioscience and Pulse Bioscience. Dr. Wagner is an employee of Orbis Health Solutions. Dr. Peoples is employed by Orbis Health Solutions and Cancer Insight; is a consultant for Rapamycin Holdings, Heat Biologics, Abexxa Biologics, and Pelican Therapeutics; and has received funding from the above as well as Sellas Life Sciences and Genentech. Dr Jakub served on a Novartis Melanoma Surgical Oncology Advisory Board. Dr. Clifton is employed by Parthenon Therapeutics. All remaining authors have declared no conflicts of interest.

Tumor Lysate Particle Only Vaccine (TLPO) vs. Tumor Lysate Particle-Loaded, Dendritic Cell Vaccine (TLPLDC) to Prevent Recurrence in Resected Stage III/IV Melanoma Patients: Results of a Phase I/IIa Trial

Status:

Version 1

Abstract

Background:

Methods:

Results:

Conclusions:

Trial Registration

Figures

Introduction

Methods

Patients

Patient randomization

Safety Monitoring and Follow-up

Vaccine production

Analysis Plan

Results

Demographics

Primary Safety Endpoints

Secondary Survival Endpoints

Subgroup Analyses

Discussion

Conclusion

Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

Version 1