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Table of Contents

    Topic review

    Cancer Vaccines

    Subjects: Oncology
    View times: 16
    Submitted by: Brigida Anna Maiorano
    (This entry belongs to Entry Collection "Solid Tumors ")

    Definition

    Therapeutic cancer vaccines target TAAs alongside adjuvant molecules that can elicit specific antibodies or cytotoxic immune responses against cancer cells. There are different ways to present TAAs to the immune system. DNA and RNA encoding TAAs or whole peptides can be recognized and processed by the APCs; tumor cell lines express TAAs and can chemotactically attract APCs; viral vectors transfect APCs after being loaded with prespecified antigens; finally, DCs act as APCs and can be loaded with TAAs.

    1. Introduction

    Immunotherapy has represented a breakthrough therapy for many cancer subtypes in the last years. Among genitourinary (GU) neoplasms, the urothelial carcinoma (UC) and the renal cell carcinoma (RCC) have benefitted mainly from immune checkpoint inhibitors (ICIs) both as single agents and in combination with other ICIs or tyrosine kinase inhibitors (TKIs) [1][2][3][4][5][6][7][8][9][10][11][12][13]. However, in prostate cancer (PCa), ICIs have shown limited efficacy primarily due to an immunologically ‘cold’ and immunosuppressive tumor microenvironment (TME) [14][15][16][17][18].
    Improving immunotherapy efficacy requires combination therapies or different pharmacological approaches [19]. In fact, the two principal ways to enhance the immune system’s antitumor activity are blocking the immune-suppressive signals responsible for the decreased antitumor response (that is, how ICIs work) or stimulating the immune activation against specific tumor-associated antigens (TAAs). The latter is the mechanism used by anticancer vaccines, capable of triggering the immune response actively by administering antigens conjugated with co-stimulatory molecules or loaded on patients’ immune cells [20][21][22][23]. In this way, antigen-presenting cells (APCs) can recognize, uptake, process, and present TAAs to naïve T-cells. Generally, intracellular antigens are presented with the class I major histocompatibility complex (MHC) molecules to CD8+ cells, turning them into effector cytotoxic lymphocytes (CTLs) [24]. It is more difficult to elicit a cytotoxic response in the case of extracellular antigens. The class II MHC molecules usually present them to CD4+ cells [24][25]. However, APCs—especially dendritic cells (DCs)—can process and present some extracellular antigens through the class I MHC to CD8+ cells, a process known as antigen cross-presentation whose discovery has been of great importance for therapeutic vaccines development [25].

    2. Vaccine Therapy in Prostate Cancer (PCa)

    PCa represents the most frequent tumor and the second leading cause of death among the Western male population [26]. PCa is an ideal candidate for vaccine therapies, given its high targetable number of TAAs, prostatic acid phosphatase (PAP), prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) among the most important [27][28]. The majority of studies focused on mCRPC. Only three phase III trials have been conducted. Even if specific immune activation was detectable, vaccines usually did not determine significant survival improvement (Table 1).

    3. Vaccine Therapy in Urothelial Cancer (UC)

    UC has a long and successful history of vaccines use, starting from the Bacillus Calmette–Guerin (BCG), which represents a cornerstone for the treatment of non-muscle invasive bladder cancer (NMIBC) since the 1990s [29]. However, BCG failure occurs in 20–50% of patients [30]. Intending to potentiate BCG efficacy, in a randomized phase I study (NCT01498172), 24 NMIBC patients received a vaccine containing the recombinant MAGE-A3 protein + the adjuvant AS15 before BCG instillations. In half of the patients, specific T-cells were subsequently detectable in blood. No survival data are available [31].
    Some UC TAAs have been tested mainly on DCs or as peptide vaccines, inducing immune responses with controversial survival effects in phase I/II trials (Table 1). Survivin-2B80-88 improved OS in phase I (p = 0.0009) [32]. CDX-1307, targeting the mannose receptor, induced immune responses in bladder cancer (BCa), but it did not get over phase I because the N-ABLE NCT01094496 phase II study was stopped early due to slow enrollment [33]. DCs loaded with Wilms tumor (WT)-1 in seven patients with mUC or mRCC determined specific immune responses and decreased T-regs [34]. S-288310, derived from DEP domain-containing 1 (DEPDC1) and M-phase phosphoprotein 1 (MPHOSPH1), was administered to pretreated mUC patients in a phase I/II trial: 89% of patients developed specific T-cells, reaching mOS of 14.4 mos, with better results if a double induction against both peptides was obtained [35]. NEO-PV-01 peptide derives by the genomic profiling of patients’ BCa: in a phase Ib trial, 10/14 patients achieved PR or stable disease (SD) [36].
    The PPV strategy has been evaluated in the platinum-progressing mUC. A phase I trial did not meet its primary endpoint of prolonging PFS among 80 BCa patients; however, a significantly longer OS was reached than best supportive care (7.9 vs. 4.1 mos; p = 0.049) [37]. In a phase II trial enrolling 48 patients with metastatic upper tract urothelial cancer (mUTUC), the development of specific T-cells was associated with longer OS (p = 0019). A median OS of 7.7 mos was achieved, reaching 13.0 mos if salvage chemotherapy was associated [38]. Finally, among 12 mUC patients, a phase I trial reported one complete response (CR), one PR, two SDs, mPFS of 3 mos, and mOS of 8.9 mos [39].
    Current trials are ongoing: the peptide vaccine ARG1 (targeting arginase-1) is under evaluation as a single agent in a phase I trial (NCT03689192); the NCT03715985 study is evaluating the multi-peptides neo-antigen vaccine NeoPepVac in combination with anti-PD1/PD-L1 in many solid tumors, including mUC (Table 2).

    4. Vaccine Therapy in Renal Cell Cancer (RCC)

    In the mRCC, different DCs and peptide vaccines have been tested, mostly in phase I/II trials, with only two published phase III studies (Table 1). With a similar Sipuleucel-T mechanism, Rocapuldencel-T is composed of DCs plus amplified tumor RNA plus CD40L RNA. In the ADAPT phase III trial, 462 patients were randomized 2:1 to receive Rocapuldencel-T plus sunitinib versus standard of care. Even if immune responses were recorded, the trial failed its primary endpoint of improving OS compared to the control group (mOS 27.7 vs. 32.4 mos; HR = 1.10, 95% CI, 0.83–1.40). Still, a trend toward better OS was evidenced in the case of more robust immune responses [40]. In the adjuvant setting, autologous-antigens loaded DCs plus cytokine-induced killer cells (CIK) were compared to α-interferon (IFN) in 410 patients, improving PFS and OS (3-year OS rate 96% vs. 83%; 5-year OS rate 96% vs. 74%; p < 0.01) [41].
    Among the peptide vaccines, EC90, a folate-targeted vaccine, plus α-IFN and IL-2, induced seven SDs and one PR in 24 patients in a phase I/II study [42]. Nine patients with progressive mRCC, treated with hypoxia-inducible protein-2 (HIG-2) peptide vaccine obtained a DCR of 77.8% and an mPFS of 10.3 mos [43]. GX301 vaccine is composed by four telomerase peptides plus Imiquimod and Montanide ISA-51 as adjuvant [44]. Telomerase contributes to tumor immortalization, but it is not expressed by somatic cells [45]. GX301 induced specific immunological responses in over 2/3 of vaccinated mRCC or mCRPC patients, with a trend for better OS (around 11 mos) [44].
    Among the different subtypes of renal cancer, clear-cell renal cell carcinoma (ccRCC) is exceptionally responsive to immunotherapy and has been historically considered the ideal subtype to treat with vaccines [46]. However, in the IMPRINT phase III trial, IMA901 (composed of 10 tumors-associated peptides) plus GM-CSF, cyclophosphamide and sunitinib did not improve OS for the 339 randomized patients in the first-line setting (mOS 33.2 vs. 33.7 mos; HR = 1.34, 95% CI, 0.96–1.86; p = 0.087), even if immune activation had previously been evidenced in phase II [47][48]. PPV with vascular endothelial growth factor receptor (VEGFR)-1 was administered in 18 ccRCC patients. Among them, two PRs and five SDs with a median duration of response of 16.5 mos were observed [49]. TG-4010 is an MVA vector-based vaccine of IL-2 and MUC-1 that induced an mOS of 19.3 mos among the 27 ccRCC patients in a phase II trial [50].
    Aiming to identify predictive biomarkers for therapeutic vaccines, blood parameters at baseline (platelets, neutrophils, monocytes, hemoglobin, and LDH), the presence of bone metastases, the MSKCC score, the Fuhrman grade, and the ECOG-performance status have been investigated in RCC [51][52][41].
    Novel vaccine targets have been proposed for future clinical studies: hypoxia-inducible factor (HIF)-1α, being the RCC often associated with the mutation of Von Hippel-Lindau (VHL) gene and dependent on the upregulation of HIF; PD-L1 derived peptides, as RCC is sensitive to immunotherapy control [53][54]. Among the ongoing trials, NCT02950766 evaluates the neo-antigen NeoVax plus Ipilimumab (phase I); the NCT03289962 phase I study is testing the vaccine RO7198457 plus atezolizumab; the NCT03294083 phase Ib trial is assessing the Pexa-Vec vaccine (Thymidine Kinase-Deactivated Vaccinia Virus) plus the anti-PD1 Cemiplimab. Finally, the NCT02643303 phase I/II study evaluates the combination of tremelimumab as in situ vaccination, durvalumab and the TME modulator polyICLC, in subjects with advanced solid tumors, including RCC, UC, PCa and testicular cancer (Table 2).
    Table 1. Vaccine therapies in genitourinary malignancies. Principal TAAs and key findings of the studies with therapeutic cancer vaccines are reported.
    TAA Vaccine Name Type of Vaccine Combination Population Phase Key Findings Reference
    PAP Sipuleucel-T (Provenge®) DC / mCRPC III mOS: 25.8 vs. 21.7 mos (HR = 0.78; 95% CI, 0.61–0.98; p = 0.03); no PFS improvement; lower baseline PSA levels predictive of OS [55][56]
    ADT nmCRPC II Humoral response with Sipuleucel-T→ADT than vice versa, related to longer TTP for PSA (p = 0.007) [57]
    Abiraterone mCRPC II Immune responses, not reduced by prednisone [58]
    Ipilimumab mCRPC I >4 years OS in 6/9 pts [59][60]
    / Neoadjuvant PCa II T-cells activation in tumor biopsies [61]
    pTVG-HP DNA / mCRPC   PSA decline in ~60% patients [62]
    Pembrolizumab Recurrent PCa II No MFS improvement [63]
    PSA PROSTVAC (PSA-TRICOM) Viral vector / mCRPC III No survival improvement; early terminated [64]
    /(intraprostatic) Recurrent PCa I Increased CD4+/CD8+ in tumor biopsies, PSA SD in 10/19 pts [65][66]
    Ipilimumab mCRPC I PSA decline in ~50% pts, low PD1+ /high CTLA4 Tregs associated with longer OS [67][68]
    PSMA   DNA / nmCRPC I/II PSA-DT 16.8 vs. 12.0 mos (p = 0.0417) [69]
    VRP / mCRPC I Antibodies production; no clinical benefit [70]
    PSA + PSMA INP-5150 DNA / nmCRPC I/II 18 mos PFS rate: 85% [71]
    PSMA + Survivin   DC (vs. Docetaxel + prednisone) mCRPC I ORR: 72.7% vs. 45.4% [72]
    PSMA + PS + PSCA + STEAP1 CV-9103 RNA / mCRPC I/II Immune responses [73]
    AR pTGV-AR DNA / mHSPC I Longer PSA-PFS in case of T-cells activation (p = 0.003) [74]
    MUC1   DC / nmCRPC I/II Improved PSA-DT (p = 0.037) [75]
    MUC1 + PSA + Brachyury   Viral / mCRPC I PSA decline in 2/12 pts [76]
    MUC1 + IL2 TG-4010 Viral vector / ccRCC II mOS: 19.3 mos [50]
    NY-ESO-1   Peptide / Stage IV PCa I T-cell responses in 9/12 pts, no survival data [77]
    NY-ESO-1 + MAGE-C2 + MUC1   DC / mCRPC IIa T-cell responses in ~30% pts, related to radiological responses [78]
    HER-2 AE37 Peptide / HER-2+ PCa I Long memory (4 years) with multiple boosters; pre-existing immunity related to PFS, TGF-β inversely related to OS, HLA-A*24/DRB1*11 related to OS [79][80][81][82]
    CDCA1   Peptide / mCRPC I mOS: 11 mos [83]
    UV1   Peptide / mHSPC I Immune responses in 85.7%, PSA declining in 64% pts [84]
    TARP   Peptide + DC / D0 PCa I Specific immune responses, reduced PSA velocity [85]
    RhoC   Peptide / PCa after RP I/II CD4+ responses in 18/21 pts [86]
    5T4   Double viral vector / Neoadjuvant, active surveillance—PCa I T-cell responses before RP and during active surveillance [87]
    TroVax Viral Docetaxel mCRPC II mPFS: 9.67 mos (vs. 5.1 docetaxel alone; p = 0.097), related to baseline PSA [52][88]
    Modified PCa cells GVAX Cell line Docetaxel Neoadjuvant PCa II Gleason score downstaging in 4/6 pts [89][90]
    Degarelix + cyclo-phosphamide Neoadjuvant PCa I/II Immune responses [91]
    PPV   Peptide / mCRPC III No survival advantage (HR = 1.04; p = 0.77); OS benefit with very low/high baseline lymphocytes [92][93][94][95]
    DCvac DC Docetaxel mCRPC II Immune responses, no survival advantage [96]
      Peptide / BCa I mOS: 7.9 mos (vs. 4.1 BSC; p = 0.049), no PFS advantage [37]
      Alone or plus chemotherapy mUTUC II Longer OS in case of immune response (p = 0.019); mOS: 7.7 mos (13.0 mos plus CT); [38]
    Peptide / mUC I 1/12 CR, 1/12 PR, 2/12 SD, mPFS 3 mos, mOS 8.9 mos [39]
    20-peptides KRM-20 Peptide / mCRPC I 2/17 PR, 1/17 PSA stability [97]
    Docetaxel + dexamethasone mCRPC II Increased specific antibodies and T-cells, no PSA/OS differences vs. PBO [98]
    MAGE-A3   Peptide Before BCG NMIBC I Specific T-cells in ~50% pts, no survival data [31]
    Survivin   Peptide / mUC I, II Improved OS (p = 0.0009) [32]
    Mannose receptor CDX-1307 Peptide / mUC I Immune responses, early stopping of phase II due to slow enrollment [33]
    WT1   DC / mUC, mRCC I/II Specific immune responses, decreased Tregs [34]
    DEPDC1 + MPHOSPH1 S-288310 Double peptide / mUC I/II mOS: 14.4 mos, better results with immune response against two peptides [35]
    NEO-PV-01   Peptide / BCa Ib PR/SD in 10/14 pts [36]
    CD40L + RCC RNA Rocapuldencel-T DC + RNA Sunitinib mRCC III No OS improvement over Sunitinib (mOS 27.7 vs. 32.4 mos; HR = 1.1, 95% ci, 0.83–1.40); trend for better OS in case of robust immune response [40]
    Autologous antigens   DC CIK Resected RCC III Compared to α-IFN, PFS improvement; 3-year OS rate 96% vs. 83%; 5-year OS rate 96% vs. 74%; p < 0.01 [41]
    Folate EC-90 Peptide α-IFN, IL-2 mRCC I/II 7/24 SD, 1/24 PR [42]
    HIG-2   Peptide / mRCC I DCR 77.8%, mPFS 10.3 mos [43]
    Telomerase GX301 Peptide / mRCC, mCRPC I/II Immune responses with trend for better OS (~11 mos) [44]
    10-peptides IMA901 Peptide Sunitinib ccRCC III No OS advantage (mOS 33.2 vs. 33.7 mos; HR = 1.34, 95% CI, 0.96–1.86; p = 0.087) [47][48]
    VEGFR1   Peptide / ccRCC I 2/18 PR, 5/18 SD, mDOR 16.5 mos [49]

    AR, androgen receptor; BCa, bladder cancer; ccRCC, clear-cell renal cell carcinoma; CDCA1, cell division associated 1; CI, confidence interval; CIK, cytokine-induced killer cells; CR, complete response; CT, chemotherapy; DC, dendritic cells; DCR, disease-control rate; DEPDC1, DEP domain-containing 1; GM-CSF, granulocyte–macrophage colony-stimulating factor; HER-2, human epidermal growth factor receptor 2; HIG-2, hypoxia-inducible protein 2; HR, hazard ratio; IFN, interferon; IL, interleukin; MAGE, melanoma-associated antigen; mCRPC, metastatic castration resistant prostate cancer; mDOR, median duration of response; MFS, metastasis-free survival; mHSPC, metastatic hormone sensitive prostate cancer; mOS, median overall survival; m PFS, median progression-free survival; MPHOSPH1, M-phase phosphoprotein 1; mRCC, metastatic renal cell cancer; mUC, metastatic urothelial cancer; MUC1, mucin-1; mUTUC, metastatic upper tract urothelial cancer; nmCRPC, non-metastatic castration resistant prostate cancer; NMIBC, non-muscle invasive bladder cancer; ORR, overall response rate; PAP, prostatic acid phosphatase; PBO, placebo; PCa, prostate cancer; PPV, personalized peptide vaccination; PR, partial response; PSA, prostate specific antigen; PSA-DT, PSA doubling time; PSCA, prostate stem cell antigen; RhoC, Ras homolog gene family member C; RP, radical prostatectomy; SD, stable disease; STEAP1, six-transmembrane epithelial antigen of the prostate-1;TAA, tumor-associated antigens; TARP, T-cell receptor gamma chain alternate reading frame protein; TGF, transforming growth factor; TTP, time to progression; VEGFR, vascular endothelial growth factor receptor; VRP, viral replicon vector; WT, Wilms tumor.

    Table 2. Ongoing trials with therapeutic vaccines and their combinations in genitourinary malignancies.
    Clinicaltrials.gov Registration Number Phase Setting Vaccine Antigen Combination
    NCT01804465 II mCRPC Sipuleucel-T PAP Ipilimumab (immediate vs. delayed)
    NCT02463799 II mCRPC Sipuleucel-T PAP Radium-223
    NCT01881867 II mCRPC Sipuleucel-T PAP Glycosylated recombinant human IL-7
    NCT03600350 II nmCRPC pTGV-HP PAP Nivolumab
    NCT04090528 II mCRPC pTGV-HP + pTGV-AR PAP, AR Pembrolizumab
    NCT02933255 I/II NAD PCa PROSTVAC PSA Nivolumab
    NCT03532217 I mHSPC PROSTVAC PSA Neoantigen DNA vaccine, Nivolumab, Ipilimumab
    NCT02649855 II mHSPC PROSTVAC PSA Docetaxel
    NCT03315871 II nmCPRC PROSTVAC PSA M7824 (anti-PD-L1/TGF-βR2), CV301
    NCT02325557 (KEYNOTE-146) I/II mCRPC ADX31-142 PSA Pembrolizumab
    NCT02362451 II nmCRPC TARP DC TARP /
    NCT02111577 III mCRPC DCvac PPV Docetaxel vs. PBO
    NCT03412786 I mHSPC Bcl-xl_42-CAF09b peptide vaccine BCl-xl /
    NCT04701021 I Relapsing PCa after RP TENDU peptide conjugate TET /
    NCT04114825 II Biochemical recurrent PCa after RT/RP RV001V peptide vaccine RhoC /
    NCT03493945 I/II mCRPC BN-Brachyury Brachyury M7824, ALT-803, Epacadostat
    NCT03689192 I mUC ARG1 Arginase-1 /
    NCT03715985 I/II mUC NeoPepVac Personalized neoantigen Anti-PD1/PD-L1
    NCT02950766 I mRCC NeoVax Personalized neoantigen Ipilimumab
    NCT03289962 I mRCC RO7198457 20 TAAs Atezolizumab
    NCT03294083 Ib mRCC Pexa-Vec Thymidine-kinase Cemiplimab
    NCT02643303 I/II Advanced RCC, UC, PCa, testicular cancer In situ vaccination with tremelimumab   Durvalumab, polyICLC
    AR, androgen receptor; BCl-xl, B-cell lymphoma extra-large protein; IL, interleukin; mCRPC, metastatic castration resistant prostate cancer; mHSPC, metastatic hormone sensitive prostate cancer; mRCC, metastatic renal cell carcinoma; mUC, metastatic urothelial carcinoma; NAD, neo-adjuvant; nmCRPC, non-metastatic castration resistant prostate cancer; PAP, prostatic acid phosphatase; PCa, prostate cancer; PD1, programmed death 1; PD-L1, programmed death-ligand 1; PPV, personalized peptide vaccination; PSA, prostate specific antigen; RhoC, Ras homolog gene family member C; RP, radical prostatectomy; RT, radiotherapy; TAA, tumor-associated antigen; TARP, T-cell receptor gamma chain alternate reading frame protein; TET, tetanus-epitope targeting; TGF, transforming growth factor.

    The entry is from 10.3390/vaccines9060623

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