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. Author manuscript; available in PMC: 2020 Jul 1.
Published in final edited form as: Surg Oncol Clin N Am. 2019 Apr 15;28(3):337–351. doi: 10.1016/j.soc.2019.02.003

Vaccine Strategy in Melanoma

Minyoung Kwak 1,2,4,*, Katie M Leick 1,3,4,*, Marit M Melssen 1,5,6, Craig L Slingluff Jr 1,4
PMCID: PMC6763732  NIHMSID: NIHMS1024576  PMID: 31079792

SYNOPSIS

The incidence of melanoma continues to increase even as advances in immunotherapy have led to survival benefits in advanced stages. Vaccines are capable of inducing strong, anti-tumor immune responses with limited toxicity. Some vaccines have demonstrated clinical benefit in clinical trials alone; however, others have not despite inducing strong immune responses. Recent advancements have improved vaccine design, while combining vaccines with other immunotherapies offers promise. This review highlights the underlying principles of vaccine development, common components of vaccines, the remaining challenges and future directions of vaccine therapy in melanoma.

Keywords: Melanoma, Vaccine, Tumor-Associated Antigen, Neoantigen, Vaccine Adjuvant, T cell

Introduction

The development of vaccines against cancer has driven significant advancements in the field of tumor immunology, leading to a better understanding of the immune response against cancer. There is new expertise on the nature of tumor-associated antigens, making it possible to even genetically engineer immunogenic antigens for melanoma vaccines. This has been achieved through advances in sequencing and manipulating genomes, development of algorithms to define putative T cell antigens, identification of different immune cell types, and unraveling complexities of the tumor microenvironment.

The promise of cancer vaccines is that vaccines induce targeted, tumor-specific immune responses with long-term memory in cases of recurrence or metastasis, with low risk of toxicity overall. There has been renewed focus on the potential of immunotherapy due to the recent success of checkpoint blockade therapy in advanced melanoma. When patients lack a pre-existing immune response to their cancer, they are unlikely to respond to checkpoint blockade; so, there is renewed interest in vaccines to induce antitumor immune responses that did not arise spontaneously. There is potential value of combining vaccine therapy with other immunotherapies to improve tumor control. Clinical trials implementing these combination therapies are currently underway. In this review, we summarize the current antigen and vaccine adjuvant strategies under investigation, and highlight the progress made with recent melanoma vaccine therapies in clinical trials.

Background on Tumor Antigenicity and Immune Activation

Cancer vaccines contain tumor-associated antigens and vaccine adjuvants to elicit the activation of dendritic cells and antigen-specific T cells. Initiation of the immune response against tumor cells occurs through recognition of tumor-associated antigens that must be processed and presented on MHC complexes by antigen-presenting cells (APCs) (Figure 1). Specific T cells recognize these MHC-antigen complexes leading to their activation and proliferation. Antigen presentation on MHC class I generally activates cytotoxic CD8 T cells (TCD8), whereas presentation on MHC class II activates CD4 helper T cells (TCD4). Elements of both CD8 and CD4 T cells are likely needed to mount an optimal response for tumor control and long-term memory.

Figure 1: Mechanism of immune response induction following vaccination.

Figure 1:

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Step 1. Vaccination allows tumor antigen to be taken up by antigen-presenting cells (APCs). Step 2. Adjuvant stimulation supports activation and maturation of APCs. Step 3. APCs present antigen to CD8 T cells via MHC class I and to CD4 T cells through MHC class II, resulting in their activation and proliferation and thereby launching an antitumor immune response.

Cancer vaccine formulations also incorporate ‘vaccine adjuvants’ to increase T cell stimulation by activating APCs, thereby enhancing antigen presentation and co-stimulation. Many vaccine adjuvants stimulate pattern-recognition receptors (PRRs) on APCs. These PRRs recognize PAMPs (pathogen- associated molecular patterns) or DAMPs (damage-associated molecular patterns), heat shock proteins, or reactive oxygen intermediates1. PAMPs include Toll-like receptor (TLR) agonists, such as CpG sequences. Introducing a tumor-associated antigen with vaccine adjuvants allows for an improved antigen-specific immune response to enhance tumor control.

Vaccine Strategies: Antigen

Antigens used in melanoma vaccines may be shared across patients or may be neoantigens that are uniquely expressed. Different types of antigens have been identified in melanoma (Figure 2), and are summarized below. The type of antigen that is selected can determine the tumor-specificity, type, and strength of the ensuing immune response.

Figure 2:

Figure 2:

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Different types of tumor-associated antigens in melanoma

Shared melanoma antigens

Melanocytic differentiation antigens

Melanocytic differentiation antigens are expressed by most melanoma tumors and induce T cell responses2,3. The shared aspect of these antigens enables broad application and generalization of shared antigen-targeting vaccines across multiple patients. Tyrosinase, TRP-2, Melan-A/MART-1, and gp-100 are common source proteins that are also expressed on normal melanocytes and on a few other pigmented cells. Thus, successful immune targeting of melanocytic antigens has the potential to induce autoimmunity to melanocytes. Additionally, since these antigens are present in some normal tissues, responses to them may be limited by pre-existing central tolerance4. Regardless, some vaccine and adoptive therapies targeting these antigens have been successful5,6.

Shared mutated antigens

Mutated antigens arise from acquired somatic mutations or single-nucleotide polymorphisms (SNPs) in melanoma cells and are often unique to a given patient tumor, although some are present in a fraction of patients. Because mutated antigens arise through tumorigenesis, they are absent in normal cells. BRAF, KIT, and NRAS mutations are common mutated antigens in melanoma. Antigenic BRAF peptides encompassing the V600E driver mutation of melanoma have been reported7–10, inducing BRAF-specific immune responses in humans9,10 and tumor control in mice7,8. These data support further clinical investigation of these mutated antigens in vaccines.

Cancer germ line antigens

Cancer germ line antigens are expressed in the placenta or testis as immune privileged sites11, while also being uniquely expressed in some malignant tumors. The immunogenicity and unique expression of these antigens in cancers, rather than in normal cells, provides an opportunity to elicit an antitumor immune response using vaccines. Their restricted expression justifies considering them a form of neoantigen. MAGE-A1, MAGE-A3, BAGE, GAGE, and NY-ESO-1 are a few examples of cancer germ line antigens that have been identified. Adoptive T cell therapy using T cells expressing a T cell receptor (TCR) transduced with NY-ESO-1 induced objective clinical responses in 55% of patients with advanced melanoma12. Thus, cancer germ line antigens can be effective tumor regression antigens. On the other hand, a MAGE-A3 vaccine failed to enhance survival in a phase III trial13; so, the use of cancer germ line antigens in vaccines remains to be optimized. Although some cancer germ line antigens are solely expressed on tumor cells, a few studies using adoptive T cell therapies have shown cross-reactivity with normal tissues when very high affinity TCRs are used14. Interestingly, some cancer germ line antigens may be sequestered and thus not subject to preexisting tolerance, whereas others may not be sequestered15. Understanding this phenomenon may improve selection of cancer germ line antigens for cancer vaccines.

Phosphopeptides

Phosphorylation of oncogenic proteins supports malignant transformation; thus, targeting them is a promising strategy. Phosphorylated peptides derived from those proteins can be presented by both MHC class I and II molecules, which induces an immune response to the phosphorylated peptide sequence specifically16–19. Identification of tumor-specific phosphopeptide antigens may provide opportunities for personalized immune vaccine therapies20. A first-in-humans clinical trial has recently been completed (NCT01846143).

Mutated neoantigens

The term ‘neo-antigen’ refers to newly expressed or acquired antigens, as in genomic mutations found within tumors but not in normal somatic cells. Due to its unique genetic sequence, the transcribed DNA, RNA, or translated peptide fragments can be used as a unique source of tumor-associated antigens. The advantage of these mutated neoantigens in vaccines is that it may avoid pre-existing central tolerance that is expected with shared antigens4 and should reduce risks of on-target autoimmune reactivity. Data also suggests that therapeutic T cells may respond more strongly to mutated neoantigens than to shared antigens21,22. Newer approaches have developed algorithms to predict and select advantageous immunogenic features of the mutanome. These mutated epitopes can be engineered into vaccines using a personalized approach23. A disadvantage of this personalized technique is the time required for the synthesis of personalized vaccines. Methods to predict immunogenic neoantigens were applied to patients and successfully showed immunogenicity of predicted neoantigens with promising clinical outcomes in a small number of patients23–25. However, much research still needs to be done to expand these preliminary results and to optimize immune responses to neoantigens.

Antigen Type and Adjuvants

Selection of an appropriate antigen type can influence the immune response following treatment. Vaccines may use antigen as whole tumor cells, RNA or DNA, single or multiple peptides, or APCs displaying the target antigen. Both efficacy and toxicity can be related to intrinsic immunologic potency, cross-reactivity of vaccine targets to antigen on normal cells, and associated adjuvants.

Peptide Vaccines

Peptide vaccines can be synthesized as short or long with single- or multi-peptide mixtures. Peptides are weakly immunogenic when naked peptide is used26,27; however, their use in combination with vaccine adjuvants or immune therapies induces potent, and frequently durable, T cell responses28–33.

Short Peptide Vaccines

Short peptide vaccines representing minimal CD8 epitopes (usually 9 amino acids long) thus elicit a cytotoxic TCD8 response by binding MHC class I. Their effects on TCD8 are advantageous as it activates effector cells directly, thus negating the need for further antigen processing by APCs. Immune response rates may approach 100% in humans, of which 1–5% of the TCD8 population are peptide-specific effector TCD828,29,31. Minimal epitope vaccines can induce strong TCD8 responses alone29. One study designed minimal epitope vaccines based on individual patient mutated neoantigens and generated neoantigen-specific T cell responses in all three patients, affecting 23–89% of the TCD8 population; memory T cells were present for up to 4 months34,24,35. Short peptide vaccines may be limited by proteolytic degradation36, tolerance due to suboptimal antigen presentation, and less sustained immune responses37.

Extensive work has been done with a modified gp100 peptide (gp100 209–217;209–2M) that is a modified form of peptide naturally presented by HLA-A2 to TCD8. Vaccination with gp100 209–2M alone increased peptide-specific T cells in 97% of patients31. Addition of gp100 to IL-2 in a clinical trial involving patients with advanced melanoma significantly increased clinical response rates and improved progression-free survival38,39. However, combination of gp100 peptide with checkpoint blockade therapies such as ipilimumab showed no therapeutic benefit compared to ipilimumab alone40. Mechanisms underlying this limitation have been explored in mice and suggest the addition of gp100 peptide vaccine in an antigen-depot vaccine with ipilimumab may lead to sequestration and destruction of non-gp100-specific effector T cells, particularly those effector T cells that are induced by ipilimumab41. This finding needs to be studied further in patients.

Helper Peptide Vaccines

Helper TCD4 are activated by recognition of peptide presented on class II MHC molecules and induce a multifaceted immune response by supporting APC, TCD8 effector function, and T cell memory formation. Thus, immune therapies targeting helper TCD4 offer promise for tumor control32. A peptide vaccine composed of a mixture of 6 melanoma helper peptides (6MHP) that are recognized by TCD4 has been used in clinical trials and induces a Th1 TCD4 response without increasing the proportion of Tregs (regulatory T cells). TCD8 responses also occurred via epitope spreading27. Sixty-five percent of 6MHP- treated patients with stage IV melanoma developed an immune response, and treatment with vaccine significantly improved overall survival compared to matched controls27. Patient survival was associated with antibody response rates and the formation of memory TCD4 immune responses26.

Long Peptide Vaccines

Long peptide vaccines refer to lengths of 20–30 amino acids and carry the potential benefit of activating both TCD8 and TCD4 responses. Murine work demonstrated more efficient internalization and processing of long peptides by APCs compared to protein, resulting in more sustained TCD8 activation42. A phase I clinical trial of NY-ESO-1-derived long peptide (30 amino acids) combined with adjuvant induced antigen-specific T cells only when peptide was used in combination with adjuvant, but not with peptide alone32. Vaccination with long peptide targeting up to 20 predicted personal neoantigens successfully induced neoantigen-specific TCD4 responses to 60% of antigens, while TCD8 responses were limited to only 16% of unique neoantigens, suggesting preferential activation of TCD4 by long peptides25. Additionally, 4 of 6 patients had no recurrence 25 months after vaccination, suggesting the potential for clinical benefits and long-lasting effects of long peptide vaccines25.

RNA, DNA, and Protein Vaccines

RNA or DNA encoding genes for tumor antigens or immune enhancers can be introduced into APCs or myocytes through bacterial or viral vectors to synthesize peptides and mediate a vaccine effect. Some RNA vaccines involve electroporation of APCs to enable incorporation of mRNA encoding melanoma- associated antigens or immunostimulatory ligands to facilitate antigen-specific T cell responses. In such studies, TCD8 responses were detected in 57–80% of patients, but no objective clinical responses were observed43,44. Some recent RNA vaccines are designed and personalized based on mutations expressed and identified by RNA sequencing and selected for predicted high affinity binding to MHC class I and II. These are engineered into synthetic RNA and delivered using a vaccine vehicle. The majority of responses induced were TCD4 responses23, comparable to personalized neoepitope vaccines based on mutated peptides25. Neoepitope vaccination also resulted in a broadened repertoire of T cells23. A phase I clinical trial of DNA vaccine-encoding genes for immunogenic epitopes for gp100 and TRP2 demonstrated an immune response rate of 84%, comparable to other peptide vaccines using gp10045,38. Despite induction of an immune response, DNA vaccines evoke limited objective clinical responses45.

Whole Cell Vaccines

Whole cancer cells can be integrated into vaccines and serve as a source of antigen for APC presentation. They contain numerous mutated neoantigens that are inherent to the tumor, which does not mandate that they be identified prior to designing and manufacturing the vaccine. Whole cells can be modified to express particular tumor antigens or immune enhancers to further potentiate immune responses. This type of vaccine is typically more proficient at inducing expansion of TCD4 than TCD8, resulting in an attenuated antitumor immune response. Despite whole cell vaccines showing initial promise to prolong survival with high clinical response rates, a large randomized phase III clinical trial showed no significant clinical benefit46. There is currently a phase 3 clinical trial underway (NCT01546571) using a cell-based vaccine derived from cell line supernatants containing antigens shed by tumor cells, which significantly improved disease-free survival in vaccine-treated patients in a prior phase 2 trial47.

Vaccine Strategies: Vaccine Adjuvants

Vaccine adjuvants are aimed at producing more robust immune responses by increasing antigen uptake and presentation, recruiting other immune cells, and/or forming a depot effect for sustained release of antigen48,49.

Incomplete Freund’s Adjuvant (IFA)

A common adjuvant used in peptide vaccines for melanoma is Montanide ISA 51 (Seppic, Inc), a form of Incomplete Freund’s Adjuvant (IFA). This is an oil-based agent where droplets of aqueous peptide are contained within a surrounding oil phase. This facilitates a depot effect at the vaccine site, allowing for continued antigen exposure in a stabilized oil emulsion48. In humans, immune responses to peptides in IFA were greater than peptides pulsed on APCs50,51. In mice, the depot effect of IFA may also lead to vaccine-site sequestration of activated T cells against antigen52 that may prevent T cell homing to tumor. There are data suggesting the added immunologic benefit of other adjuvants such as CD40 stimulating antibody and TLR agonists instead of IFA to avoid these concerns. Human studies have not yet been done to determine whether CD40 antibody plus TLR agonists can induce a much stronger T cell response than IFA alone; however, our studies continue to support the addition of IFA to TLR agonists in melanoma vaccines with short peptides53.

Dendritic Cell Vaccines

Dendritic cell (DC) vaccines use autologous DC to present antigen and to stimulate immune cells by releasing pro-inflammatory cytokines. In preparation for vaccine synthesis, DCs are isolated from peripheral blood. The vaccine can then be packaged using various adjuvants to induce DC activation, or autologous DCs can be pulsed with antigen ex-vivo and administered in the same patient. Vaccination route may determine the tissue site where the DCs will migrate54. A randomized phase II trial using autologous DC vaccines with GM-CSF in patients with advanced melanoma showed longer survival compared to a tumor cell vaccine, with 70% reduction in risk of death55. However, this trial had low patient numbers and unequal prognostic factors. Other trials demonstrated lower T cell responses with DC vaccines when compared to peptide vaccines with adjuvant50,51.

Another potential method of further stimulating DCs in murine models is an in-vivo method using viral vectors and CD40 stimulating antibodies. CD40 is a co-stimulatory receptor on DCs that adds to DC maturation and TCD8 activation56,57. The addition of CD40 antibody to a combination of TLR3 agonists and a neoantigen vaccine against colon adenocarcinoma in mice showed improved survival compared to either agonist alone, with expansion of neoantigen-specific T cells in both the periphery and in the tumor microenvironment58. These preclinical results show promise in the strength of CD40 for DC activation but still need to be evaluated in humans.

Toll-like Receptor (TLR) Agonists

TLR agonists stimulate PRRs on DCs to promote antigen processing and presentation to T cells. A common TLR agonist used in melanoma vaccine adjuvants is the TLR3 agonist poly-ICLC (polyinosine-polycytidylic acid). This agonist matures DCs to generate TCD8 and NK cells with higher cytotoxic capacity59,60. The combination of IFA and poly-ICLC with long NY-ESO-1 peptides showed that both adjuvants had different but beneficial effects on antigen-specific activation of TCD4: emulsification of the antigen in IFA increased antigen-specific TCD4, while poly-ICLC induced a Th1 phenotype, leading to increased cell-mediated immunity and inflammatory response61.

CpG is an oligodeoxynucleotide fragment rich in cytosine and guanine, similar to bacterial DNA that is an agonist for TLR9 and induces DC maturation62,63. With DC maturation, CpG has also been shown to increase co-stimulatory surface marker expression with increases in proinflammatory cytokines needed for cytotoxic TCD8 co-stimulation62,63, and possibly B cell stimulation64. Addition of CpG to IFA has dramatically enhanced T cell responses to a short peptide vaccine62. Despite its effectiveness in TCD8 promotion, a mouse model suggests it may require decreased levels of immunosuppressive Tregs and multiple booster vaccinations to maximize its effect65. On the other hand, resiquimod (R848) is an agonist for TLR7 and TLR8 that has been found to decrease the immunosuppressive function of Tregs66 and myeloid-derived suppressor cells (MDSC)67, supporting increased T cell proliferation.

Systemic Cytokines

Other types of vaccine adjuvants involve the use of immune cell cytokines. GM-CSF (granulocyte- macrophage colony-stimulating factor) is used to attract and activate DCs to further promote peptide antigen-specific responses68,69. GM-CSF enhanced immunogenicity of a cell-based vaccine in mice68, and combined with a peptide vaccine, increased T cell responses when compared to DCs pulsed with the same peptide antigen51. However, in a large randomized clinical trial, the addition of GM-CSF to a peptide vaccine significantly decreased responses in both TCD8 and TCD4 compared to peptide vaccine alone70. Also, another large randomized clinical trial revealed that adding GM-CSF to a melanoma cell vaccine resulted in worse survival and early melanoma-related death71. The use of GM-CSF as a vaccine adjuvant is cautionary and requires further investigation.

Systemic IL-2 infusions have also been used as a vaccine adjuvant in melanoma due to its overall stimulatory effect on T cells, and its clinical activity as high-dose monotherapy. When I L-2 was combined with the peptide vaccine gp-100, clinical responses were significantly higher than with I L-2 alone, with associated longer progression-free survival72. Peptide-specific immunogenicity occurred in 19% of patients who received both gp100 and I L-2, but this antigen specificity did not correlate with clinical response. Other studies have failed to show immunologic or clinical benefit of I L-2, GM-CSF, or interferon-alpha in combination with melanoma vaccines73,74.

Current Melanoma Vaccine Trials

There are many ongoing clinical trials studying the impacts of various antigen formats and adjuvants on immune responses and clinical outcomes (Figure 3A). Among these, DC and peptide vaccines predominate. Peptide vaccines use a variety of adjuvants, the most common of which is IFA (Figure 3B). DC vaccines, as an adjuvant on their own, do not frequently utilize additional adjuvants (Figure 3C). Combination therapy with vaccines provides an opportunity to target the immune system through another mechanism to augment anti-tumor effects and potentiate clinical benefits. The most common combination therapy for peptide vaccines is checkpoint blockade, while IL-2 is most common among combination therapies used with DC vaccines, though DC vaccines utilize more combination therapies overall (Figure 3B, C).

Figure 3: Current vaccine trials in melanoma.

Figure 3:

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The number of active clinical trials for each melanoma vaccine vehicle as of July 2018 on ClinicalTrials.gov are shown in A. Number of active trials using combination therapies and adjuvants are quantified for peptide vaccines in B and dendritic cell vaccines in C.

Novel approaches

Prophylactic melanoma vaccine

With the success of the generation of a prophylactic vaccine for virus-induced cervical cancer, the idea of prophylactic vaccines against melanoma regains interest. Preclinical in vivo studies have shown potential of this approach, regardless of whether a DC-, RNA-, whole cell- or peptide-based antigen vehicle was used75–78.

Stem cell-based vaccines

Induced pluripotent stem cells (Ipsc’s) are immunogenic pluripotent stem-like cells that can be generated from a patient’s cells. Their gene expression is similar to embryonic stem cells and includes expression of many tumor antigens. In preclinical models of melanoma and other solid tumors, immunization and therapeutic vaccination of iPSC’s induced robust TCD4 and TCD8 responses, as well as a reduction in tumor burden79. Though these studies are still in the preclinical phase, they show potential for generating effective, personalized vaccines.

Conclusions

Melanoma vaccine research has shown the potential for vaccines to elicit antigen-specific T cells as well as provide some tumor control. Understanding the importance of specific immunologic effects of antigen vehicle and adjuvant is vital to the progression of vaccine strategy. As our knowledge base expands through preclinical studies and results from recent clinical trials are finalized, we will be able to better optimize our approach for sustained tumor control.

Current therapies that involve vaccines alone have limitations due to discordance between antigen-specific T cell expansion and tumor control. Despite cancer vaccines showing lasting immune response rates up to 100%28,31, vaccines alone have led to clinical response rates below 10% in most studies80. This low clinical response may be due to insufficient T cell priming, poor homing to tumor, dysfunction of T cells in the tumor microenvironment, or progressive loss of function. Some of these may be due to defects in antigen presentation, or immunosuppressive changes in the tumor microenvironment that could lead to anergic T cells or interference with T cell homing to tumor81. The advancement of neoantigen technology, along with newer adjuvant strategies, are all promising additions to increase clinical response. There are other preclinical methods of inhibiting immunosuppressive effects currently under investigation, as well. Therefore, the combination of vaccines with other immunotherapies has clear theoretical advantages as we await results of ongoing clinical trials.

KEY POINTS.

  • Cancer vaccines are formulated with tumor-associated antigens and vaccine adjuvants to elicit a targeted immune response for tumor control.

  • The elicited T cell response to tumor-associated antigens may be discordant with tumor control; current strategies of vaccine antigens and adjuvants are under investigation to improve clinical response rates.

  • Many clinical trials are currently underway to determine the optimal combinations for the different types of tumor-associated antigens, vaccine adjuvants, and other immunotherapies such as checkpoint blockade therapy.

Name of commercial interest What I received My role When Support provided to: Scientific/research area Relevant
Celldex Research funding research support (to UVA) ongoing University of Virginia Cancer immunotherapy Yes
Celldex Consulting fee/honorarium Scientific Advisory Board honorarium 6/6/16 Self Cancer immunotherapy Yes
CureVac Consulting fee Scientific Advisory Board member Ongoing Self Cancer vaccines, using peptides Yes
Polynoma Consulting fee Principal Investigator, for phase III trial of POL-103A Ongoing University of Virginia Cancer vaccines, melanoma Yes
Glaxo Smith Kline (GSK) Research funding Funding for clinical trial of MAGE-A3 vaccine trial Mel55 (NCT01425749) Ongoing University of Virginia Cancer vaccines, vaccine adjuvants Yes
Castle Biosciences Honorarium - consulting fee Scientific advisory board meeting fall 2014 Past Self Melanoma clinical care No
Merck PD-1 antibody for use in investigator- initiated trial Principal investigator of Mel64 trial Ongoing University of Virginia Melanoma immune therapy Yes
Merck Research funding and PD-1 Ab for use in investigator- initiated trial Sponsor-investigator for PD-101 trial Ongoing University of Virginia Pancreatic cancer immune therapy Yes
Merck Research funding Biomarker study. Clinical trial in pancreatic CA Ongoing University of Virginia Immune therapy Yes
3M Resiquimod for use in Mel60 clinical trial of melanoma vaccine, with long peptides Principal investigator of Mel60 trial (funded by Melanoma Research Alliance) Ongoing University of Virginia Cancer vaccines Yes
Theraclion Staff and equipment support for AM003 trial Research Support Ongoing University of Virginia Focused ultrasound No
UVA Licensing and Ventures Group Royalties Co-inventor on peptides for use in cancer vaccines, some licensed to GSK Ongoing Self Peptide vaccines for cancer Yes
Immatics Consulting Fee Scientific Advisory Board member Ongoing, but ending 2018–19 University of Virginia Peptide vaccines for cancer Yes
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Footnotes

DISCLOSURE STATEMENT

Minyoung Kwak, Katie Leick, and Marit Melssen: nothing to disclose

Craig Slingluff, Jr: see chart below

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References

  • 1.Pradeu T, Cooper EL. The danger theory: 20 years later. Front Immunol. 2012;3:287. doi: 10.3389/fimmu.2012.00287 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Bakker AB, Schreurs MW, de Boer AJ, et al. Melanocyte lineage-specific antigen gp100 is recognized by melanoma-derived tumor-infiltrating lymphocytes. J Exp Med. 1994;179(3):1005–1009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Reynolds SR, Celis E, Sette A, et al. HLA-Independent Heterogeneity of CD8+ T Cell Responses to MAGE-3, Melan-A/MART-1, gp100, Tyrosinase, MC1R, and TRP-2 in Vaccine-Treated Melanoma Patients. The Journal of Immunology. 1998;161(12):6970–6976. [PubMed] [Google Scholar]
  • 4.Colella TA, Bullock TNJ, Russell LB, et al. Self-Tolerance to the Murine Homologue of a Tyrosinase-Derived Melanoma Antigen: Implications for Tumor Immunotherapy. Journal of Experimental Medicine. 2000;191(7):1221–1232. doi: 10.1084/jem.191.7.1221 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Rosenberg SA, Yang JC, Schwartzentruber DJ, et al. Recombinant fowlpox viruses encoding the anchor-modified gp100 melanoma antigen can generate antitumor immune responses in patients with metastatic melanoma. Clin Cancer Res. 2003;9(8):2973–2980. [PMC free article] [PubMed] [Google Scholar]
  • 6.Overwijk WW, Tsung A, Irvine KR, et al. gp100/pmel 17 is a murine tumor rejection antigen:induction of “self”-reactive, tumoricidal T cells using high-affinity, altered peptide ligand. J Exp Med. 1998;188(2):277–286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Liu Q, Zhu H, Liu Y, Musetti S, Huang L. BRAF peptide vaccine facilitates therapy of murine BRAF-mutant melanoma. Cancer Immunol Immunother. 2018;67(2):299–310. doi: 10.1007/s00262-017-2079-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Cintolo JA, Datta J, Xu S, Gupta M, Somasundaram R, Czerniecki BJ. Type I-polarized BRAF-pulsed dendritic cells induce antigen-specific CD8+ T cells that impact BRAF-mutant murine melanoma. Melanoma Res. 2016;26(1):1–11. doi: 10.1097/CMR.0000000000000203 [DOI] [PubMed] [Google Scholar]
  • 9.Somasundaram R, Swoboda R, Caputo L, et al. Human leukocyte antigen-A2-restricted CTL responses to mutated BRAF peptides in melanoma patients. Cancer Res. 2006;66(6):3287–3293. doi: 10.1158/0008-5472.CAN-05-1932 [DOI] [PubMed] [Google Scholar]
  • 10.Sharkey MS, Lizee G, Gonzales MI, Patel S, Topalian SL. CD4(+) T-cell recognition of mutated B-RAF in melanoma patients harboring the V599E mutation. Cancer Res. 2004;64(5):1595–1599. [DOI] [PubMed] [Google Scholar]
  • 11.Fijak M, Bhushan S, Meinhardt A. Immunoprivileged sites: the testis. Methods Mol Biol. 2011;677:459–470. doi: 10.1007/978-1-60761-869-0_29 [DOI] [PubMed] [Google Scholar]
  • 12.Robbins PF, Kassim SH, Tran TLN, et al. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin Cancer Res. 2015;21(5):1019–1027. doi: 10.1158/1078-0432.CCR-14-2708 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Dreno B, Thompson JF, Smithers BM, et al. MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial. The Lancet Oncology. 2018;19(7):916–929. doi: 10.1016/S1470-2045(18)30254-7 [DOI] [PubMed] [Google Scholar]
  • 14.Johnson LA, Morgan RA, Dudley ME, et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood. 2009;114(3):535–546. doi: 10.1182/blood-2009-03-211714 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Tung KSK, Harakal J, Qiao H, et al. Egress of sperm autoantigen from seminiferous tubules maintains systemic tolerance. J Clin Invest. 2017;127(3):1046–1060. doi: 10.1172/JCI89927 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Petersen J, Wurzbacher SJ, Williamson NA, et al. Phosphorylated self-peptides alter human leukocyte antigen class I-restricted antigen presentation and generate tumor-specific epitopes. Proc Natl Acad Sci USA. 2009;106(8):2776–2781. doi: 10.1073/pnas.0812901106 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Mohammed F, Cobbold M, Zarling AL, et al. Phosphorylation-dependent interaction between antigenic peptides and MHC class I: a molecular basis for the presentation of transformed self. Nat Immunol. 2008;9(11):1236–1243. doi: 10.1038/ni.1660 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Depontieu FR, Qian J, Zarling AL, et al. Identification of tumor-associated, MHC class II-restricted phosphopeptides as targets for immunotherapy. Proc Natl Acad Sci USA. 2009;106(29):12073–12078. doi: 10.1073/pnas.0903852106 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Mohammed F, Stones DH, Zarling AL, et al. The antigenic identity of human class I MHC phosphopeptides is critically dependent upon phosphorylation status. Oncotarget. 2017;8(33):54160–54172. doi: 10.18632/oncotarget.16952 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Zarling AL, Obeng RC, Desch AN, et al. MHC-restricted phosphopeptides from insulin receptor substrate-2 and CDC25b offer broad-based immunotherapeutic agents for cancer. Cancer Res. 2014;74(23):6784–6795. doi: 10.1158/0008-5472.CAN-14-0043 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Robbins PF, Lu Y-C, El-Gamil M, et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat Med. 2013;19(6):747–752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Lu Y-C, Yao X, Crystal JS, et al. Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions. Clin Cancer Res. 2014;20(13):3401–3410. doi: 10.1158/1078-0432.CCR-14-0433 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Sahin U, Derhovanessian E, Miller M, et al. Personalized RNA mutanome vaccines mobilize poly specific therapeutic immunity against cancer. Nature. 2017;547(7662):222–226. doi: 10.1038/nature23003 [DOI] [PubMed] [Google Scholar]
  • 24.Carreno BM, Magrini V, Becker-Hapak M, et al. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science. 2015;348(6236):803–808. doi: 10.1126/science.aaa3828 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Ott PA, Hu Z, Keskin DB, et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature. 2017;547(7662):217–221. doi: 10.1038/nature22991 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Reed CM, Cresce ND, Mauldin IS, Slingluff CL, Olson WC. Vaccination with Melanoma Helper Peptides Induces Antibody Responses Associated with Improved Overall Survival. Clin Cancer Res. 2015;21(17):3879–3887. doi: 10.1158/1078-0432.CCR-15-0233 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Hu Y, Kim H, Blackwell CM, Slingluff CL. Long-term outcomes of helper peptide vaccination for metastatic melanoma. Ann Surg. 2015;262(3):456–464; discussion 462–464. doi: 10.1097/SLA.0000000000001419 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Slingluff CL, Petroni GR, Chianese-Bullock KA, et al. Immunologic and clinical outcomes of a randomized phase II trial of two multipeptide vaccines for melanoma in the adjuvant setting. Clin Cancer Res. 2007;13(21):6386–6395. doi: 10.1158/1078-0432.CCR-07-0486 [DOI] [PubMed] [Google Scholar]
  • 29.Slingluff CL, Petroni GR, Olson WC, et al. Effect of granulocyte/macrophage colony-stimulating factor on circulating CD8+ and CD4+ T-cell responses to a multipeptide melanoma vaccine: outcome of a multicenter randomized trial. Clin Cancer Res. 2009;15(22):7036–7044. doi: 10.1158/1078-0432.CCR-09-1544 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Slingluff CL, Petroni GR, Chianese-Bullock KA, et al. Randomized multicenter trial of the effects of melanoma-associated helper peptides and cyclophosphamide on the immunogenicity of a multipeptide melanoma vaccine. J Clin Oncol. 2011;29(21):2924–2932. doi: 10.1200/JCO.2010.33.8053 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Rosenberg SA, Sherry RM, Morton KE, et al. Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma. J Immunol. 2005;175(9):6169–6176. [DOI] [PubMed] [Google Scholar]
  • 32.Sabbatini P, Tsuji T, Ferran L, et al. Phase I trial of overlapping long peptides from a tumor self- antigen and poly-ICLC shows rapid induction of integrated immune response in ovarian cancer patients. Clin Cancer Res. 2012;18(23):6497–6508. doi: 10.1158/1078-0432.CCR-12-2189 [DOI] [PubMed] [Google Scholar]
  • 33.Slingluff CL, Chianese-Bullock KA, Bullock TNJ, et al. Immunity to melanoma antigens: from self-tolerance to immunotherapy. Adv Immunol. 2006;90:243–295. doi: 10.1016/S0065-2776(06)90007-8 [DOI] [PubMed] [Google Scholar]
  • 34.Nitschke NJ, Bjoern J, Iversen TZ, Andersen MH, Svane IM. Indoleamine 2,3-dioxygenase and survivin peptide vaccine combined with temozolomide in metastatic melanoma. Stem Cell Investig. 2017;4. doi: 10.21037/sci.2017.08.06 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Zeng G, Li Y, El-Gamil M, et al. Generation of NY-ESO-1-specific CD4+ and CD8+ T Cells by a Single Peptide with Dual MHC Class I and Class II Specificities: A New Strategy for Vaccine Design. Cancer Res. 2002;62(13):3630–3635. [PMC free article] [PubMed] [Google Scholar]
  • 36.Brinckerhoff LH, Kalashnikov VV, Thompson LW, et al. Terminal modifications inhibit proteolytic degradation of an immunogenic MART-1(27–35) peptide: implications for peptide vaccines. Int J Cancer. 1999;83(3):326–334. [DOI] [PubMed] [Google Scholar]
  • 37.Knutson KL, Schiffman K, Cheever MA, Disis ML. Immunization of cancer patients with a HER-2/neu, HLA-A2 peptide, p369–377, results in short-lived peptide-specific immunity. Clin Cancer Res. 2002;8(5):1014–1018. [PubMed] [Google Scholar]
  • 38.Schwartzentruber DJ, Lawson DH, Richards JM, et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011;364(22):2119–2127. doi: 10.1056/NEJMoa1012863 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Kawakami Y, Eliyahu S, Jennings C, et al. Recognition of multiple epitopes in the human melanoma antigen gp100 by tumor-infiltrating T lymphocytes associated with in vivo tumor regression. J Immunol. 1995;154(8):3961–3968. [PubMed] [Google Scholar]
  • 40.Hodi FS, O’Day SJ, McDermott DF, et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med. 2010;363(8):711–723. doi: 10.1056/NEJMoa1003466 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Hailemichael Y, Woods A, Fu T, et al. Cancer vaccine formulation dictates synergy with CTLA-4 and PD-L1 checkpoint blockade therapy. J Clin Invest. 128(4):1338–1354. doi: 10.1172/JCI93303 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Bijker MS, van den Eeden SJF, Franken KL, Melief CJM, Offringa R, van der Burg SH. CD8+ CTL priming by exact peptide epitopes in incomplete Freund’s adjuvant induces a vanishing CTL response, whereas long peptides induce sustained CTL reactivity. J Immunol. 2007;179(8):5033–5040. [DOI] [PubMed] [Google Scholar]
  • 43.Wilgenhof S, Van Nuffel AMT, Corthals J, et al. Therapeutic vaccination with an autologous mRNA electroporated dendritic cell vaccine in patients with advanced melanoma. J Immunother. 2011;34(5):448–456. doi: 10.1097/CJI.0b013e31821dcb31 [DOI] [PubMed] [Google Scholar]
  • 44.Wilgenhof S, Van Nuffel AMT, Benteyn D, et al. A phase IB study on intravenous synthetic mRNA electroporated dendritic cell immunotherapy in pretreated advanced melanoma patients. Ann Oncol. 2013;24(10):2686–2693. doi: 10.1093/annonc/mdt245 [DOI] [PubMed] [Google Scholar]
  • 45.Patel PM, Ottensmeier CH, Mulatero C, et al. Targeting gp100 and TRP-2 with a DNA vaccine: Incorporating T cell epitopes with a human IgG1 antibody induces potent T cell responses that are associated with favourable clinical outcome in a phase I/II trial. Oncoimmunology. 2018;7(6):e1433516. doi: 10.1080/2162402X.2018.1433516 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Faries MB, Mozzillo N, Kashani-Sabet M, et al. Long-Term Survival after Complete Surgical Resection and Adjuvant Immunotherapy for Distant Melanoma Metastases. Ann Surg Oncol. 2017;24(13):3991–4000. doi: 10.1245/s10434-017-6072-3 [DOI] [PubMed] [Google Scholar]
  • 47.Bystryn JC, Zeleniuch-Jacquotte A, Oratz R, Shapiro RL, Harris MN, Roses DF. Double-blind trial of a polyvalent, shed-antigen, melanoma vaccine. Clin Cancer Res. 2001;7(7):1882–1887. [PubMed] [Google Scholar]
  • 48.Awate S, Babiuk LA, Mutwiri G. Mechanisms of Action of Adjuvants. Front Immunol. 2013;4. doi: 10.3389/fimmu.2013.00114 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Temizoz B, Kuroda E, Ishii KJ. Vaccine adjuvants as potential cancer immunotherapeutics. Int Immunol. 2016;28(7):329–338. doi: 10.1093/intimm/dxw015 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.O’Neill DW, Adams S, Goldberg JD, et al. Comparison of the immunogenicity of Montanide ISA 51 adjuvant and cytokine-matured dendritic cells in a randomized controlled clinical trial of melanoma vaccines. JCO. 2009;27(15S):3002–3002. doi: 10.1200/jco.2009.27.15s.3002 [DOI] [Google Scholar]
  • 51.Slingluff CL, Petroni GR, Yamshchikov GV, et al. Clinical and immunologic results of a randomized phase II trial of vaccination using four melanoma peptides either administered in granulocyte- macrophage colony-stimulating factor in adjuvant or pulsed on dendritic cells. J Clin Oncol. 2003;21(21):4016–4026. doi: 10.1200/jc0.2003.10.005 [DOI] [PubMed] [Google Scholar]
  • 52.Hailemichael Y, Dai Z, Jaffarzad N, et al. Persistent antigen at vaccination sites induces tumor-specific CD8+ T cell sequestration, dysfunction and deletion. Nat Med. 2013;19(4):465–472. doi: 10.1038/nm.3105 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Melssen M, Petroni G, Grosh WW, et al. A multipeptide vaccine plus toll-like receptor (TLR) agonists LPS or polylCLC in combination with incomplete Freund’s adjuvant (IFA) in melanoma patients. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) 2016;4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Mullins DW, Sheasley SL, Ream RM, Bullock TNJ, Fu Y-X, Engelhard VH. Route of Immunization with Peptide-pulsed Dendritic Cells Controls the Distribution of Memory and Effector T Cells in Lymphoid Tissues and Determines the Pattern of Regional Tumor Control. J Exp Med. 2003;198(7):1023–1034. doi: 10.1084/jem.20021348 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Dillman RO, Cornforth AN, Nistor GI, McClay EF, Amatruda TT, Depriest C. Randomized phase II trial of autologous dendritic cell vaccines versus autologous tumor cell vaccines in metastatic melanoma: 5-year follow up and additional analyses. J Immunother Cancer. 2018;6(1):19. doi: 10.1186/s40425-018-0330-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Tacken PJ, de Vries IJM, Torensma R, Figdor CG. Dendritic-cell immunotherapy: from ex vivo loading to in vivo targeting. Nature Reviews Immunology. 2007;7(10):790–802. doi: 10.1038/nri2173 [DOI] [PubMed] [Google Scholar]
  • 57.Hangalapura BN, Timares L, Oosterhoff D, Scheper RJ, Curiel DT, de Gruijl TD. CD40-targeted adenoviral cancer vaccines: the long and winding road to the clinic. J Gene Med. 2012;14(6):416–427. doi: 10.1002/jgm.1648 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Hoki T, Yamauchi T, Odunsi K, Ito F. Synergistic anti-tumor efficacy of combined TLR3 and CD40 neoantigen vaccine requires Batf3-dependent dendritic cells. The Journal of Immunology. 2018;200(1 Supplement):181.7–181.7. [Google Scholar]
  • 59.Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001;413(6857):732–738. doi: 10.1038/35099560 [DOI] [PubMed] [Google Scholar]
  • 60.Perrot I, Deauvieau F, Massacrier C, et al. TLR3 and Rig-like receptor on myeloid dendritic cells and Rig-like receptor on human NK cells are both mandatory for production of IFN-gamma in response to double-stranded RNA. J Immunol. 2010;185(4):2080–2088. doi: 10.4049/jimmunol.1000532 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Tsuji T, Sabbatini P, Jungbluth AA, et al. Effect of Montanide and poly-ICLC adjuvant on human self/tumor antigen-specific CD4+ T cells in phase I overlapping long peptide vaccine trial. Cancer Immunol Res. 2013;1(5):340–350. doi: 10.1158/2326-6066.CIR-13-0089 [DOI] [PubMed] [Google Scholar]
  • 62.Speiser DE, Liénard D, Rufer N, et al. Rapid and strong human CD8+ T cell responses to vaccination with peptide, I FA, and CpG oligodeoxynucleotide 7909. J Clin Invest. 2005;115(3):739–746. doi: 10.1172/JCI23373 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Haining WN, Davies J, Kanzler H, et al. CpG oligodeoxynucleotides alter lymphocyte and dendritic cell trafficking in humans. Clin Cancer Res. 2008;14(17):5626–5634. doi: 10.1158/1078-0432.CCR- 08–0526 [DOI] [PubMed] [Google Scholar]
  • 64.Krieg AM. CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol. 2002;20:709–760. doi: 10.1146/annurev.immunol.20.100301.064842 [DOI] [PubMed] [Google Scholar]
  • 65.Nava-Parada P, Forni G, Knutson KL, Pease LR, Celis E. Peptide vaccine given with a Toll-like receptor agonist is effective for the treatment and prevention of spontaneous breast tumors. Cancer Res. 2007;67(3):1326–1334. doi: 10.1158/0008-5472.CAN-06-3290 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Peng G, Guo Z, Kiniwa Y, et al. Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science. 2005;309(5739):1380–1384. doi: 10.1126/science.1113401 [DOI] [PubMed] [Google Scholar]
  • 67.Lee M, Park C-S, Lee Y-R, Im S-A, Song S, Lee C-K. Resiquimod, a TLR7/8 agonist, promotes differentiation of myeloid-derived suppressor cells into macrophages and dendritic cells. Arch Pharm Res. 2014;37(9):1234–1240. doi: 10.1007/s12272-014-0379-4 [DOI] [PubMed] [Google Scholar]
  • 68.Dranoff G, Jaffee E, Lazenby A, et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA. 1993;90(8):3539–3543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Ahlers JD, Dunlop N, Alling DW, Nara PL, Berzofsky JA. Cytokine-in-adjuvant steering of the immune response phenotype to HIV-1 vaccine constructs: granulocyte-macrophage colony-stimulating factor and TNF-alpha synergize with IL-12 to enhance induction of cytotoxic T lymphocytes. J Immunol. 1997;158(8):3947–3958. [PubMed] [Google Scholar]
  • 70.Slingluff CL, Petroni GR, Smolkin ME, et al. IMMUNOGENICITY FOR CD8+ AND CD4+ T CELLS OF TWO FORMULATIONS OF AN INCOMPLETE FREUND’S ADJUVANT FOR MULTIPEPTIDE MELANOMA VACCINES. J Immunother. 2010;33(6):630–638. doi: 10.1097/CJI.0b013e3181e311ac [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Faries MB, Hsueh EC, Ye X, Hoban M, Morton DL. Effect of granulocyte/macrophage colony-stimulating factor on vaccination with an allogeneic whole-cell melanoma vaccine. Clin Cancer Res. 2009;15(22):7029–7035. doi: 10.1158/1078-0432.CCR-09-1540 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Schwartzentruber DJ, Lawson DH, Richards JM, et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011;364(22):2119–2127. doi: 10.1056/NEJMoa1012863 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Kirkwood JM, Lee S, Land S, et al. E1696: Final analysis of the clinical and immunological results of a multicenter ECOG phase II trial of multi-epitope peptide vaccination for stage IV melanoma with MART-1 (27–35), gp100 (209–217, 210M), and tyrosinase (368–376, 370D) (MGT) +/− IFNa2b and GM-CSF. JCO. 2004;22(14_suppl):7502–7502. doi: 10.1200/jco.2004.22.14_suppl.7502 [DOI] [Google Scholar]
  • 74.Slingluff CL, Petroni GR, Yamshchikov GV, et al. Immunologic and clinical outcomes of vaccination with a multiepitope melanoma peptide vaccine plus low-dose interleukin-2 administered either concurrently or on a delayed schedule. J Clin Oncol. 2004;22(22):4474–4485. doi: 10.1200/JCO.2004.10.212 [DOI] [PubMed] [Google Scholar]
  • 75.Riemann H, Takao J, Shellman YG, et al. Generation of a prophylactic melanoma vaccine using whole recombinant yeast expressing MART-1. Exp Dermatol. 2007;16(10):814–822. doi: 10.1111/j.1600-0625.2007.00599.x [DOI] [PubMed] [Google Scholar]
  • 76.Markov OV, Mironova NL, Sennikov SV, Vlassov VV, Zenkova MA. Prophylactic Dendritic Cell-Based Vaccines Efficiently Inhibit Metastases in Murine Metastatic Melanoma. PLOS ONE. 2015;10(9):e0136911. doi: 10.1371/journal.pone.0136911 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Phua KKL, Staats HF, Leong KW, Nair SK. Intranasal mRNA nanoparticle vaccination induces prophylactic and therapeutic anti-tumor immunity. Scientific Reports. 2014;4:5128. doi: 10.1038/srep05128 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.van Elsas A, Sutmuller RPM, Hurwitz AA, et al. Elucidating the Autoimmune and Antitumor Effector Mechanisms of a Treatment Based on Cytotoxic T Lymphocyte Antigen-4 Blockade in Combination with a B16 Melanoma Vaccine: Comparison of Prophylaxis and Therapy. Journal of Experimental Medicine. 2001;194(4):481–490. doi: 10.1084/jem.194.4.481 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Kooreman NG, Kim Y, de Almeida PE, et al. Autologous iPSC-Based Vaccines Elicit Anti-tumor Responses In Vivo. Cell Stem Cell. 2018;22(4):501–513.e7. doi: 10.1016/j.stem.2018.01.016 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med. 2004;10(9):909–915. doi: 10.1038/nm1100 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Boon T, Coulie PG, Van den Eynde BJ, van der Bruggen P. Human T cell responses against melanoma. Annu Rev Immunol. 2006;24:175–208. doi: 10.1146/annurev.immunol.24.021605.090733 [DOI] [PubMed] [Google Scholar]

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