Cancer Vaccines

INTRODUCTION

Cancer immunotherapy, or immuno-oncology, is a rapidly growing field of cancer research dedicated to developing novel cancer therapies by understanding and harnessing immune pathways. While 20^th-century oncology was transformed by the discovery of cytotoxic chemotherapy and, later, targeted agents, the first systematic study of immuno-oncology predated the discovery of nitrogen mustards and folic acid antagonists by four decades.¹ In 1891, Dr. William B. Coley, the “Father of Immunotherapy,” noted the beneficial effect of erysipelas and fever on malignant tumors.² In his capacity as chief bone surgeon at Memorial Hospital in New York, Coley inoculated sarcoma patients with Streptococcus pyogenes and Serratia marcescens.^3–5 Interest in Coley’s primitive cancer vaccine waxed and waned until a 1962 controlled study by Johnston et al. posthumously validated Coley when his immune-stimulating inoculations generated a 20% response rate.⁶ Studies in subsequent decades have further validated Coley’s work, and many immune therapies are now approved by the U.S. Food and Drug Administration (FDA). Following is a review of the basic principles behind contemporary vaccine development and the future of therapeutic vaccine research.

HISTORICAL ORIGINS OF VACCINATION

The term “vaccine” is derived from the Latin “vacca,” or cow, a reference to the English physician Edward Jenner’s original cowpox vaccine. In 1796, Jenner extracted fluid from a cowpox pustule on the hand of an infected milkmaid and inoculated a healthy 8-year-old boy with the fluid. When the boy was variolated with smallpox shortly thereafter, he did not develop the disease.⁷ Jenner’s case series of 10 successfully vaccinated patients⁸ paved the way for the modern era of vaccination, culminating two centuries later with the World Health Organization’s 1979 declaration of the global eradication of smallpox.⁹

PROPHYLACTIC VS. THERAPEUTIC VACCINES

Cancer vaccines are subclassified as either therapeutic or prophylactic interventions. Prophylactic vaccines are forms of primary and secondary cancer prevention, aimed at reducing cancer incidence, morbidity, and mortality. Prophylactic cancer vaccines have proven successful for the primary prevention of hepatocellular carcinoma secondary to hepatitis B virus and squamous cell carcinoma secondary to human papillomavirus (HPV). Whereas prophylactic vaccines such as Jenner’s cowpox vaccine are given to healthy people to prevent future disease,¹⁰ therapeutic vaccines are given to treat existing malignancy. It is important to note that adjuvant vaccination strategies intended to prevent relapse or metastatic disease are considered therapeutic, despite their technical designation as tertiary cancer prevention.¹⁰

VACCINE TARGETS

Therapeutic cancer vaccines can target a spectrum of antigens expressed by tumor cells. The first cancer vaccines used whole-cell preparations administered in combination with an adjuvant or virus to generate an enhanced immune response. Recent research has uncovered a wide variety of potential targets for cancer vaccines. Newer vaccines target tumor-specific antigens (TSAs), which are uniquely expressed in tumor cells, or tumor-associated antigens (TAAs), which are expressed at low levels in both tumor cells and healthy cells.¹¹ Well known targets include mutated oncoproteins such as p53, ras, and B-Raf that result from point mutations and fusions. There are overexpressed antigens such as mucin 1 (MUC1) and human epidermal growth factor receptor (EGFR), and oncofetal antigens such as carcinoembryonic antigen (CEA) and alpha- fetoprotein. Viral antigens associated with HPV and hepatitis viruses can be targeted, as can tissue lineage and differentiation antigens such as prostatic acid phosphatase (PAP), prostate- specific antigen (PSA), glycoprotein 100 (gp100), and melanoma antigen recognized by T-cells 1 (MART-1).¹² Cancer-testis (CT) antigens are promising targets expressed in male germ cells in healthy adults and in multiple cancer types.¹³ CT antigens under investigation include melanoma-associated antigen 1 (MAGE) and New York esophageal carcinoma antigen 1 (NY-ESO-1). Vascular endothelial growth factor receptor-directed vaccines can target the tumor microenvironment.¹⁴ Vaccines can also target cancer stem cells and interrupt the process of invasion and metastasis via recently discovered antigens like brachyury, a driver of epithelial-mesenchymal transition.¹⁵ In addition to TSAs and TAAs, personalized therapeutic cancer vaccines, as monotherapy or in combination with other therapies,¹⁶ can immunize patients against their own neoepitopes (mutated antigens produced by an individual tumor). This can eventually activate effector T-cells and kill tumors.

VACCINE PLATFORMS

Current cancer vaccines vary not only by target antigens and immune adjuvants, but also by vaccine platforms, including such broad platforms as peptides/proteins, whole tumor cells, recombinant vectors, dendritic cells (DCs), gangliosides, and genes. Each has advantages and disadvantages.

The most common vaccine platform is peptides/proteins. These vaccines are relatively simple and economical to develop. However, the simplicity of a platform may prove problematic if its short amino acid sequence fails to encode sufficient antigenic material to induce an immune response. Thus, peptide vaccines usually require an immune adjuvant. Given their larger amino acid sequence, protein vaccines are more costly to produce than peptide vaccines, but they may provoke a stronger response.¹⁷ Both peptide and protein vaccines are population-restricted by human leukocyte antigen.

Whole tumor-cell vaccines, subclassified as either autologous or allogeneic,¹⁸ can present a wide variety of TAAs. This lack of specificity may dilute the immune response, however, necessitating additional stimulation via granulocyte-macrophage colony-stimulating factor (GM-CSF) or Bacillus Calmette-Guerin (BCG). Autologous vaccines, first tested in 1978,¹⁹ are typically irradiated and require an adjuvant.²⁰ Autologous vaccines require tumor procurement from the patient, which is not always feasible. GM-CSF-transduced autologous tumor-cell vaccines have been investigated extensively, but none is currently FDA-approved.²¹ Allogeneic whole tumor-cell vaccines contain several established malignant cell lines, offering an unlimited supply of tumor antigen at reduced cost. However, promising phase II studies have been followed by negative phase III trials, so that no allogeneic whole tumor-cell vaccine is currently FDA-approved.²²

Recombinant poxvirus vaccines appear safe and can express substantial amounts of foreign DNA. Numerous ongoing trials are investigating recombinant vectors, most using modified poxviruses such as vaccinia or avipoxvirus. The immunogenic efficacy of vaccinia is self-limiting, however, and the host generally neutralizes the virus after one or two vaccinations.¹²

DCs are professional antigen-presenting cells (APCs) that activate T-lymphocytes through major histocompatibility complex (MHC) signaling.²³ Autologous DC vaccines can be pulsed with peptide or protein or infected with a viral vector. DC vaccines require complicated preparation, but the platform has proven successful. In 2010, the FDA approved sipuleucel-T (PROVENGE®) for metastatic castration-resistant prostate cancer (mCRPC).²⁴

Gangliosides are glycolipids that are overexpressed in several tumor types.²⁵ While ganglioside-targeting monoclonal antibodies (dinutuximab) are FDA-approved,²⁶ prior phase III clinical trials of vaccine monotherapies targeting these tumor antigens were negative.^27,28

Genetic vaccines use viral or plasmid vectors to transfect RNA or DNA into host somatic cells that directly produce the desired target antigen. DNA vaccination has proven simple, stable, cost-effective, and safe. The platform is, however, limited by weak immunogenicity through a strong host cellular immune response and will likely require additional priming techniques to be successful.²⁹

APPROVED THERAPEUTIC CANCER VACCINES

Therapeutic cancer vaccines are currently FDA-approved for the treatment of early-stage bladder cancer, mCRPC, and metastatic melanoma.

TheraCys® and TICE®

TheraCys (intravesical BCG live; Sanofi Pasteur) was approved by the FDA in 1990 for intravesical use in the treatment and prophylaxis of urothelial carcinoma in situ of the urinary bladder and for prophylaxis of primary or recurrent stage Ta and/or T1 urothelial carcinoma following transurethral resection.³⁰ A multicenter, randomized, open-label, phase III trial comparing intravesical BCG vaccine and intravesical doxorubicin demonstrated a 5-year disease-free survival of 45% for BCG recipients vs. 18% for doxorubicin recipients.³¹ The therapeutic benefit of BCG vaccine was confirmed by a subsequent metanalysis that showed a 27% reduction in the risk of disease progression for BCG (hazard ratio [HR] 0.73; P = 0.001).³² Following supply shortages, production of TheraCys was discontinued; a competing strain of BCG vaccine (TICE; Merck) is now available.³³

PROVENGE

Sipuleucel-T (PROVENGE; Dendreon Corporation) was approved by the FDA in April 2010. PROVENGE is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic mCRPC.²⁴ Autologous peripheral blood mononuclear cells, including APCs, are obtained via leukapheresis, then cultured with PA2024, the fusion product of the recombinant tumor antigen PAP and APC-activating GM-CSF. During a 40-hour incubation, APCs process the recombinant antigen into peptides presented on their surface to effect MHC signaling and T-cell activation. Each dose of vaccine contains a minimum of 50 million autologous CD54+ (intercellular adhesion molecule 1 [ICAM-1])³⁴ cells activated with PAP-GM-CSF. Patients receive 3 doses given at 2-week intervals. The FDA initially rejected PROVENGE in 2007 after two phase III trials (D9901,³⁵ D9902A³⁶) failed to meet their primary endpoints of progression-free survival (PFS). Analysis of the combined dataset demonstrated a 33% reduction in risk of death for PROVENGE (P = 0.011), leading to a third randomized phase III trial (D9902B, IMPACT)³⁷ with a primary endpoint of overall survival (OS) rather than PFS. Kantoff et al. demonstrated median OS of 25.8 months in the sipuleucel-T group vs. 21.7 months in the placebo group, a 4.1-month benefit. There was a 22% relative reduction in risk of death with a HR of 0.78 (95% confidence interval [CI], 0.61–0.98; P = 0.03).

IMLYGIC®

IMLYGIC (talimogene laherparepvec; Amgen), or T-VEC, is a genetically modified oncolytic viral therapy approved by the FDA in 2015 for the treatment of advanced melanoma.³⁸ Considered a type of therapeutic cancer vaccine, T-VEC represents a novel drug class using a genetically modified, live, attenuated herpesvirus that expresses GM-CSF. T-VEC has a dual mechanism of action, mediating both local and systemic immune responses. T-VEC is injected into unresectable cutaneous, subcutaneous, or nodal lesions in patients with recurrent melanoma, which produces a local tumoricidal effect through viral replication and cell lysis. GM-CSF produced during viral replication enhances T-cell priming by APCs that present tumor antigens released during viral-mediated tumor lysis. Tumor antigen-loaded DCs migrate systemically and effect a distant immune response, although responses in injected tumor are superior to those of distant metastases.³⁹ After the initial treatment, subsequent doses of T-VEC can be administered at 3-week (dose 2) and 2-week (dose 3 and beyond) intervals for 6 months, or until no treatable lesions remain. FDA approval in 2015 followed a randomized, open-label, phase III trial (OPTiM, n = 436)⁴⁰ comparing intralesional T-VEC to subcutaneous GM-CSF. The primary endpoint of durable response rate (DRR) was defined as the percent of patients with complete response or partial response maintained continuously for a minimum of 6 months. T-VEC resulted in both higher DRR and longer median OS. DRR in the T-VEC group was 16.3% vs. % in the GM-CSF group (P < 0.001), with an overall response rate (ORR) of 26% vs. 6%, respectively. Median OS was 23.3 months (95% CI, 19.5–29.6 months) with T-VEC and 18.9 months (95% CI, 16.0–23.7 months) with GM-CSF (HR 0.79; 95% CI, 0.62–1.00; P = 0.051).

THERAPEUTIC VACCINE CLINICAL TRIALS

Experience

Other than trials of BCG, sipuleucel-T, and T-VEC, phase III trials of cancer vaccine monotherapies have been largely negative (Table 1), despite these therapies being generally well tolerated with favorable side-effect profiles. Experience from these trials has shown that the kinetics of a clinical response to a therapeutic vaccine monotherapy are different from the kinetics of a response to cytotoxic chemotherapy, and that PFS is a poor proxy for clinical efficacy.⁴¹ Fundamental differences between cytotoxic chemotherapy and cancer vaccine therapies account for the differing kinetics of response. While chemotherapy attacks the tumor and its microenvironment, vaccines target the immune system itself. Chemotherapy can work quickly, but its tumoricidal properties are transient, limited by pharmacokinetics, drug half-life and toxicity. In contrast, vaccines effect a delayed, memory immune response that may yield a distant survival benefit by precluding the spread and survival of micrometastatic disease.⁴² The terms epitope spreading, antigen spreading, and antigen cascade all describe the broad T-cell response to non-vaccine tumor antigens that follows vaccine-mediated tumor lysis.⁴³ Antigen cascade may allow for the successful recognition and cross-priming of patient-specific tumor neoantigens, yielding a durable immune response that is more clinically meaningful than the initial response to the vaccine’s targeted epitopes.⁴⁴ Both vaccine kinetics and clinical experience suggest that vaccine therapies are most effective in patients with good performance status, limited tumor burden, and slowly progressive, early-stage disease. While complex immune endpoints resulting from antigen cascade are active targets of investigation, OS remains the best surrogate for clinical efficacy and the primary endpoint of most active vaccine trials.

Table 1.

Selected negative phase III clinical trials of therapeutic cancer vaccines

Vaccine	Vaccine Platform	Patient Population	Trial	Year
PSA-TRICOM (PROSTVAC)	Recombinant viral (vaccinia and fowlpox)	mCRPC	PROSPECT66 NCT01322490	2018
recMAGE-A3 + AS15 (GSK 2132231A)	Protein (MAGE-A3 CT antigen)	Melanoma	DERMA67 NCT00796445	2018
Canvaxin + BCG	Allogeneic whole tumor cell	Melanoma	NCT0005215668	2017
Rindopepimut (CDX-110)	Peptide (EGFR)	Glioblastoma	ACT IV69 NCT01480479	2017
IMA901	Peptide	RCC	IMPRINT70 NCT01265901	2016
Multiepitope peptide	Peptide (MART-1/gp100/tyrosinase)	Melanoma	NCT0198957271	2015
Belagenpumatucel-L (Lucanix)	Allogeneic whole tumor cell	NSCLC	NCT0067650772	2015
Tecemotide (Stimuvax/L-BLP25)	Peptide (MUC1)	NSCLC	START73 NCT00409188	2014
Gp100	Peptide (gp100)	Melanoma	NCT0009465374	2010
GVAX	Recombinant DNA (GM-CSF)	mCRPC	VITAL-175 & VITAL-276 NCT00089856 (terminated for futility)	2008
Bec2 + BCG	Ganglioside	SCLC	SILVA77 NCT00003279	2008

GVAX: GM-CSF-transduced autologous tumor-cell vaccine; NSCLC: non-small cell lung cancer; RCC: renal cell carcinoma; SCLC: small cell lung cancer

Current Strategies

As of October 2018, there are 522 active interventional studies of cancer vaccines (351 in the United States; 91 in Europe; 50 in China) available for review on clinicaltrials.gov. Current trials seek to improve therapeutic vaccine efficacy either by targeting novel tumor antigens or employing vaccines in combination with other therapeutic approaches (Figure 1). Combination strategies typically include chemotherapy, radiotherapy (RT), endocrine therapy, small-molecule inhibitors, cytokines, or immune checkpoint inhibitors (ICI). These therapies often exert secondary immune-mediated antineoplastic effects, and novel trials seek to exploit potential synergistic responses. For example, RT is an effective local anticancer therapy with known immune pathway synergies. While the local tumoricidal effect of ionizing radiation is due to direct DNA damage and free radical production, RT has been shown to improve control of both locoregional and distant systemic disease. The abscopal effect (a term derived from the Latin words for “off target”) was first described in 1953⁴⁵ following the observation that ionizing radiation slowed tumor growth outside of the radiation field. By 2004, the effect was shown to be immune-mediated.⁴⁶ RT effects an immune response when tumor antigens are released from dying tumor cells and form an in-situ vaccine.⁴⁷ RT monotherapy also generates maturation stimuli required for DC activation of T-lymphocytes. RT upregulates the expression of MHC class I molecules, calreticulin, and high-mobility group box 1 (HMGB1) protein.⁴⁸ MHC class I is required to effect a T-cell-mediated response against tumor, and neoplastic cells often downregulate MHC expression as a means of immune evasion. Calreticulin is a calcium-binding chaperone that assists production of both MHC class I proteins and tapasin, a co-factor required for MHC assembly. Calreticulin promotes phagocytic uptake of TAAs, and an increase in calreticulin is associated with antitumor immunity.⁴⁹ HMGB1 is a highly conserved nuclear protein that acts as a pro-inflammatory cytokine stimulating the local production of tumor-necrosis factor (TNF), interleukin-6, and interferon-γ (IFN-γ). DNA damage from radiation leads to the sequestration of HMGB1 in the cell nucleus, which leads to an increase in hypermutated immunoglobulins and DCs.⁵⁰ HMGB1 acts as a tumor suppressor by binding to Rb and causing G1 cell cycle arrest and apoptosis.⁵¹ Combination vaccine studies of radiosensitizing immunotherapy (Table 2) seek to build upon the abscopal effect and represent one direction of ongoing therapeutic vaccine research.

Figure 1.

Multimodal immunotherapy via multiple synergistic pathways can improve therapeutic vaccine efficacy. Vaccines targeting novel antigens (brachyury) generate antigen-specific T-cell mediated response. Immune checkpoint inhibitors block PD-1, PD-L1, and CTLA-4 and inhibit immunosuppressive pathways that allow cancer cell evasion. TGF-β neutralization exerts a negative effect on activity of immunosuppressive Tregs and when combined with an ICI (M7824) enables T-cell infiltration of tumor. Stimulatory cytokines (ALT-803) enhance NK-cell-mediated cytotoxicity. Inhibition of the IDO enzyme (epacodostat) downregulates immunosuppressive pathways. Immunogenic tumor cell death releases tumor neoantigens and increases downstream cross-priming of further T-cell response.

Courtesy of Z. Folzenlogen, MD, Denver, CO.

Table 2.

Selected clinical trials of therapeutic cancer vaccines in combination with radiation

Vaccine	Combination Interventions	Cancer Type	Phase	Identifier
Intravesical BCG	Durvalumab + EBRT	Bladder	I/II	NCT03317158
Autologous DC- adenovirus p53 vaccine	Cyclophosphamide + surgery + RT	Breast	I/II	NCT00082641
Yeast-brachyury peptide vaccine (GI-6301)	Aldoxorubicin hydrochloride HCI, ALT- 803, ETBX-051, ETBX- 061, GI-6301, haNK, avelumab, cetuximab, cyclophosphamide, SBRT	Chordoma	I/II	NCT03647423
Yeast-brachyury peptide vaccine (GI-6301)	RT	Chordoma	II	NCT02383498
Personalized neoantigen vaccine (NeoVax)	Temozolomide + RT + pembrolizumab	Glioma	I	NCT02287428
Autologous DCs pulsed with lysate derived from an allogeneic glioblastoma stem-like cell line	Temozolomide + RT ± bevacizumab	Glioma	I	NCT02010606
HSPPC-96	Surgery + RT	Glioma	I	NCT02722512
HSPPC-96	Surgery + RT + temozolomide + pembrolizumab	Glioma	II	NCT03018288
GVAX	Vaccine + chemo + RT	Pancreas	Pilot	NCT00727441
GVAX	Adjuvant FOLFIRINOX + SBRT + cyclophosphamide	Pancreas	Pilot	NCT01595321
GVAX	Neoadjuvant cyclophosphamide + SBRT + nivolumab	Pancreas	II	NCT03161379
GVAX	Adjuvant cyclophosphamide + SBRT + pembrolizumab	Pancreas	II	NCT02648282
ProstAtak® (AdV-tk)	RT + valacyclovir	Prostate	III	NCT01436968

EBRT: external beam radiation therapy; GVAX: allogeneic GM-CSF-transduced pancreatic tumor cell vaccine; HSPPC-96: heat shock protein peptide complex-96; SBRT: stereotactic body radiation therapy

Systemic standard-of-care anticancer therapies such as chemotherapy, endocrine therapies, and small molecule targeted agents may potentiate the antitumor effects of immunotherapy (as summarized in Table 3), and vice versa.¹² Many trials of ICIs have been negative, with approvals generally limited to hot tumors—those prone to immune recognition due to high mutational load and increased tumor neoantigen expression. Most tumors remain cold, however, unseen by the immune system. An unfavorable tumor microenvironment and low levels of circulating lymphocytes mean ICIs are often ineffective. Novel combination strategies using therapeutic cancer vaccines offer the potential to turn cold tumors hot. Like RT, cytotoxic chemotherapy can induce immunogenic tumor cell death through downstream cross-priming of released tumor antigens by APCs and T-cell activation. Chemotherapy can decrease populations of immunosuppressive regulatory T-cells (Tregs)⁵² or modulate their function. Small molecules like sunitinib also decrease populations of Tregs and myeloid-derived suppressor cells (MDSC); BCL-2 inhibitors increase the ratio of CD8+ cells to Tregs. Endocrine therapies can induce thymic regeneration, with increased numbers of naïve T-cells. Like RT, systemic radionuclide therapies can upregulate expression of the Fas death receptor on tumor cells. Fas, or CD95, is a cell surface protein that belongs to the TNF receptor family that mediates apoptosis and is often downregulated by cancer cells as a mechanism of immune evasion.⁵³ Therapeutic vaccine trials exploring immune synergies with standard-of-care therapies are ongoing.

Table 3.

Cancer therapies with known immune synergies

Anticancer Therapy	Mechanism of action to enhance vaccine efficacy
Oxaliplatin Anthracyclines	↑ release of tumor antigen following cell death ↑ cross-priming of TAA by DC ↑ T-cell activation
Docetaxel	↓Tregs Modulates CD4+, CD8+, CD19+, NK (natural killer) Enhances CD8+ response to CD3 cross linking
Paclitaxel	↑ T-helper type I cytokine production patterns (IFN-γ and IL-2) ↑ CD44 in CD4+ and CD8+ effector T cells
Cisplatin Vinorelbine	↑ CD4+ T-cell : Treg
Cyclophosphamide	↓ Treg function ↑ CD4+ T-cell development Modulates DC maturation and function
Fludarabine	↓ Tregs
5-FU	↓ MDSC ↑ IFN-γ production by intratumoral CD8 + T cells
Temozolomide	Induces autophagy
Radiation Therapy	↑ release of tumor antigen following cell death (abscopal effect) ↑ cross-priming of TAA by DC ↑ T-cell activation ↑ Calreticulin expression → ↑ MHC class I ↑ tapasin ↑ phagocytosis
Radionuclide Therapy	↑ Fas, CEA, MUC-1, MHC class I, ICAM-1
Endocrine Therapy	↑ thymic regeneration → ↑ naïve T-cells
Sunitinib	↓ Tregs ↓ MDSC ↑ intratumoral infiltration of activated T-lymphocytes
BCL-2 inhibitors	↑ CD8+ T-cell : Treg

Antigen cascade following therapeutic vaccination generates a population of tumor antigen-specific T-cells. Most contemporary vaccine trials are investigating strategies of immunogenic intensification⁵⁴ through combined immune therapies that expand and facilitate this T-cell population while preventing immune tolerance and evasion. Phase I and II clinical trials exploring combinations of FDA-approved vaccines (sipuleucel-T, T-VEC) and FDA-approved ICIs (ipilimumab, pembrolizumab, nivolumab) have already demonstrated robust responses in combination arms.⁵⁵ Trials of vaccines in combination with antibodies to programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are generally more mature than those using FDA-approved anti- programmed death-ligand 1 (PD-L1) antibodies (avelumab, atezolizumab, durvalumab). Comprehensive reviews are available that detail these combined modality studies.^55,56 Novel non-FDA approved vaccines are also finding success in combination with ICIs. An open label phase II clinical trial (NCT02426892)⁵⁷ investigating a peptide vaccine (ISA101) targeting HPV oncoproteins E6 and E7 in patients with incurable HPV-16+ solid tumors recently demonstrated that the addition of the vaccine to nivolumab generated an ORR of 33%, superior to that of single-agent anti-PD-1 antibodies previously tested in similar patient populations (CheckMate 141).⁵⁸

Research from our group suggests that even deeper immunogenic intensification is possible through the concurrent use of multiple therapeutic classes. The National Cancer Institute’s (NCI) intramural program has opened multidrug trials including QuEST1 (NCT03493945), a phase I/II trial of a brachyury-targeted vaccine in combination with M7824, ALT-803, and epacadostat. BN-Brachyury is a novel recombinant vector-based therapeutic cancer vaccine designed to induce an enhanced immune response against brachyury, which is overexpressed in many solid tumor types and is a transcription factor promoting epithelial-to-mesenchymal transition and metastatic spread.¹⁵ M7824 is a bifunctional fusion protein consisting of an anti-PD-L1 antibody and the extracellular domain of transforming growth factor beta (TGF-β) receptor type 2, a TGF-β trap. TGF-β inhibits the immune response via multiple pathways, including expansion of Tregs,⁵⁹ and has been associated with metastatic progression.^60–62 M7824 can also mediate antibody-dependent cellular cytotoxicity (ADCC) in vitro. ALT-803 is an IL-15/IL-15Rα cytokine superagonist complex that can enhance natural killer cell-mediated ADCC and T-cell cytotoxicity.⁶³ Epacadostat (INCB024360) is an orally available inhibitor of indoleamine 2,3-dioxygenase, a tryptophan pathway enzyme overexpressed in many solid tumors that enhances immune escape.⁶⁴ Using a similar multimodality approach, NCT03050814 is a randomized phase II trial of a therapeutic vaccine (Ad-CEA) in combination with an anti-PD-L1 monoclonal antibody (avelumab) and standard-of-care chemotherapy (FOLFOX) for patients with metastatic colorectal cancer. Our group is also exploring intralesional vs. systemic vaccine delivery as well as immunogenic intensification through novel combinations of multiple viral vectors and tumor antigens. NCT03481816 is a dose-escalation study of three separate adenovirus-vectored vaccines, each individually targeting the human TAAs PSA, MUC1, and brachyury. NCT03349983 is a dose-escalation study of two recombinant viral vectors (modified vaccinia Ankara and fowlpox) that express the T-cell costimulatory molecules B7.1, ICAM-1, and LFA-3 (designated TRICOM) and the tumor antigen brachyury.

Technological advances now allow for the processing of cold tumor into a personalized mutanome vaccine.¹⁶ First-in-human trials of these vaccines compare biopsies of cold tumor and healthy tissue with next-generation sequencing assays that allow for the detection of tumor- specific neoantigens. Computational prediction algorithms then generate targets for neoepitope vaccines. Personalized mutanome vaccines have the potential for therapeutic benefit irrespective of tumor histology or intrinsic immunogenicity. The NCI’s Surgery Branch has developed a pipeline to generate tumor neoantigens for personalized therapeutic vaccine trials. NCT03480152 is an open label, phase I/II trial that identifies neoantigens following tumor resection and isolation of tumor-infiltrating lymphocytes (TILs). Immunogenic neoantigens will be identified from TILs by high throughput immunologic screening using long peptides and tandem minigenes covering all mutated epitopes.⁶⁵ These neoantigens will form the basis of a therapeutic mRNA vaccine. A competing trial (NCT03300843) is using TILs to produce a personalized DC vaccine.

SUMMARY

Cancer vaccines represent some of the most exciting developments in oncology in the last decade. Unfortunately, their impact as monotherapy in metastatic carcinomas has been modest. As of today, we have few positive clinical trials with three therapeutic cancer vaccines approved by the FDA. Many preclinical and clinical studies have suggested that therapeutic cancer vaccines can activate effector T-cells against tumor antigens and kill targeted cells across different tumor types with minimal toxicities. Cancer vaccines also expand T-cell clones that can travel to disease sites, leading to increased tumor T-cell inflammation. Ideal additive and/or synergistic therapeutic agents in combination with cancer vaccines should be able to assist effector T-cells by neutralizing local immunosuppressive mechanisms responsible for immune escape, with the ultimate goal of engaging, expanding, and enabling the antitumor immune response.

Future clinical trials will identify the timing and sequence of the best combination strategies. Important considerations in designing those trials include:

1. adaptive design that can quickly detect the most effective combinations and eliminate nonactive ones;

2. detection and development of biomarkers of immune response;

3. optimal timing of treatment;

4. neoadjuvant studies that focus on the tumor microenvironment;

5. different vaccine platforms that can target the same antigens yet activate different T-cell populations;

6. analysis of local vs. systemic vaccine delivery methods.

One of the major concerns of combination therapy has been the possibility of increased toxicity; however, data so far suggest that combinations do not result in any additional toxicity. Combinations of different treatment modalities such as chemotherapy, hormone therapy, radiopharmaceuticals, and ICIs with cancer vaccines have proven safe in numerous trials. Results of ongoing and planned larger randomized studies will determine the future of immune-based treatment platforms.

Key Points.

• Therapeutic cancer vaccines are a promising immunotherapeutic treatment modality; however, it is unlikely that cancer vaccines given alone can dramatically change cancer outcomes.

• Multiple clinical trials have shown that vaccines are well tolerated and safe.

• Cancer vaccines can induce antigen cascade or epitope spreading, effecting a distant and durable immune response.

• Ongoing clinical trials seek to improve cancer vaccine efficacy by targeting novel antigens and by combining cancer vaccines with standard-of-care treatments and other immuno-oncology agents with the goal of generating future immune-based platforms.

• Development of successful immune-based platforms will require randomized clinical trials investigating vaccine combinations, treatment sequence, and new biomarkers of immune response.

Synopsis.

Cancer vaccines are a promising strategic approach within the rapidly growing field of immuno-oncology. Therapeutic cancer vaccines are distinct from prophylactic vaccines and vary by both target antigen and vaccine platform. There are currently three FDA-approved therapeutic cancer vaccines: intravesical BCG live, sipuleucel-T, and T-VEC. Prior clinical trials have shown that vaccines are generally well tolerated, exhibit unique kinetics, can target tumor neoantigens, and induce antigen cascade. Ongoing clinical trials seek to improve vaccine efficacy either by targeting novel antigens or by combining vaccines with standard-of-care therapies or other immune therapies.