Therapeutic cancer vaccines

Abstract

Therapeutic cancer vaccines have the potential of being integrated in the therapy of numerous cancer types and stages. The wide spectrum of vaccine platforms and vaccine targets is reviewed along with the potential for development of vaccines to target cancer cell "stemness," the epithelial-to-mesenchymal transition (EMT) phenotype, and drug-resistant populations. Preclinical and recent clinical studies are now revealing how vaccines can optimally be used with other immune-based therapies such as checkpoint inhibitors, and so-called nonimmune-based therapeutics, radiation, hormonal therapy, and certain small molecule targeted therapies; it is now being revealed that many of these traditional therapies can lyse tumor cells in a manner as to further potentiate the host immune response, alter the phenotype of nonlysed tumor cells to render them more susceptible to T-cell lysis, and/or shift the balance of effector:regulatory cells in a manner to enhance vaccine efficacy. The importance of the tumor microenvironment, the appropriate patient population, and clinical trial endpoints is also discussed in the context of optimizing patient benefit from vaccine-mediated therapy.

Keywords: Animal models; Cancer vaccines; Clinical trials; Immunotherapy; Prostate cancer; T cells; Tumor antigens.

Fig. 1

The three costimulatory molecules in TRICOM (B7.1, ICAM-1 and LFA-3) act synergistically in enhancing antigen-specific T-cell responses. Each molecule has a distinct ligand on T cells. Adapted from Schlom et al. Recombinant TRICOM-based therapeutic cancer vaccines: lessons learned (Chapter 20, pp. 309–331). In: Cancer Immunotherapy: Immune Suppression and Tumor Growth, Second Edition. G. Prendergast and E. Jaffee, eds. Elsevier Ltd. (2013).

Fig. 2

CEA-specific lymphoproliferation of T cells from CEA transgenic mice vaccinated with TRICOM vector (without the CEA transgene); rV-, rF-CEA; rV-, rF-CEA-B7.1; or rV-, rF-CEA-TRICOM vectors. Adapted from Aarts et al. (2002). Vector-based vaccine/cytokine combination therapy to enhance induction of immune responses to a self-antigen and anti-tumor activity. Cancer Res. 62, 5770–5777.

Fig. 3

The importance of vaccine-induced antigen cascade in anti-tumor immunity. Top panel: CEA transgenic (Tg) mice were transplanted subcutaneously (s.c.) with MC38-CEA⁺ tumors on day 0. A, control mice were vaccinated with PBS vehicle s.c. on day 8 and intratumorally (i.t.) on days 15 and 22. B, mice were vaccinated s.c. with rV-CEA/TRICOM on day 8 and then boosted s.c. with rF-CEA-TRICOM on days 15 and 22. C, mice were vaccinated s.c. with rV-CEA-TRICOM on day 8 and then boosted i.t. with rF-CEA-TRICOM on days 15 and 22. P values on day 28 compared with the PBS control group. Mice in C were separated into two groups (D and E) based on the tumor volume and were used for subsequent immunologic analyses after tumor transplantation. Middle panel: Induction of CD8⁺ T-cell responses to CEA, p53, and gp70 after the CEA-TRICOM vaccination. Splenic lymphocytes from CEA.Tg mice were used 29 days after tumor transplantation. A, CEA-specific CTL activity. B, p53-specific CTL activity. C, gp70-specific CTL activity. Control mice treated with PBS (○), non-responders to CEA/TRICOM vaccine therapy (▴), and responders to CEA/TRICOM vaccine therapy (▪). D-F, antigen-specific IFN-γ production from CD8⁺ T cells. G-I, antigen-specific tumor necrosis factor-α production from CD8⁺ T cells. Bottom panel: CEA.Tg mice were vaccinated with CEA-TRICOM as described. Cured mice (see panel E above) were challenged with tumor cells that were CEA⁺gp70⁺, CEA⁺gp70^neg, CEA^neggp70⁺, or CEA^neggp70^neg. The results demonstrate that some of the anti-tumor effects can be attributed to CEA in the original vaccination, but the most potent anti-tumor effects are those directed against the tumor-associated cascade antigen gp70 not in the vaccine. As a control, age/sex-matched CEA.Tg mice were implanted with the same tumors (thin lines). Adapted from Kudo-Saito et al. (2005). Induction of an antigen cascade by diversified subcutaneous/intratumoral vaccination is associated with antitumor responses. Clin Cancer Res. 11, 2416–2426.

Fig. 4

The “off-the-shelf” nature of TRICOM vaccines containing transgenes for one or more tumor-associated antigens (TAAs) and three T-cell costimulatory molecule transgenes. Prime and booster vaccinations are given subcutaneously. Adapted from Schlom et al. Recombinant TRICOM-based therapeutic cancer vaccines: lessons learned (Chapter 20, pp. 309–331). In: Cancer Immunotherapy: Immune Suppression and Tumor Growth, Second Edition. G. Prendergast and E. Jaffee, eds. Elsevier Ltd. (2013).

Fig. 5

A, Overall survival (OS) of a 43-center placebo-controlled randomized Phase II study of PROSTVAC vaccination. Kaplan-Meier estimator for PROSTVAC (rV-, rF-PSA-TRICOM) arm is shown as a solid line and estimator for the control arm is a dashed line. The small vertical tic marks show the censoring times. The estimated median OS is 25.1 months for the PROSTVAC arm and 16.6 months for the control arm (P=0.006). Adapted from Kantoff et al. (2010). Overall survival analysis of a Phase II randomized controlled trial of a poxviral-based PSA targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol. 28, 1099–1105. B, Overall survival in patients with metastatic castrate-resistant prostate cancer using the Spiluleucel-T vaccine vs. control. Sipuleucel-T improved patients’ OS (hazard ratio for death = 0.78; P = .03). Adapted from Kantoff et al. (2010). Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 363, 411–422. The placebo control consisted of cultured antigen-presenting cells (APCs) from leukapheresis, without prostatic acid phosphatase–granulocyte macrophage colony-stimulating factor (PAP–GM-CSF) antigen. Per the trial protocol, the control group could receive cryopreserved APCs with antigen upon disease progression.

Fig. 6

A, The Kaplan-Meier curve for the patients (n=32) with metastatic prostatic cancer vaccinated with rV-, rF-PSA-TRICOM (PROSTVAC) demonstrates (panel A) a median overall survival (OS) of 26.6 months. B, There was a strong trend in the ability to mount a six-fold increase in PSA–T cells post-vaccine and an increase in OS. Adapted from Gulley et al. (2010). Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer. Cancer Immunol Immunother. 2010.

Fig. 7

A, Tumor growth rates following chemotherapy vs. vaccine therapy. Adapted from data in Stein et al. (2011). Tumor regression and growth rates determined in five intramural NCI prostate cancer trials: the growth rate constant as an indicator of therapeutic efficacy. Clin Cancer Res. 17, 907–917; Gulley et al. (2011). The impact of tumour volume on potential efficacy of therapeutic vaccines. Curr Oncol. 18, e150-e157; Madan et al. (2010). Therapeutic cancer vaccines in prostate cancer: the paradox of improved survival without changes in time to progression. Oncologist. 15, 969–975. A, Average tumor growth rates and time to death in patients with metastatic prostate cancer, from five clinical trials (four with chemotherapy and one with PROSTVAC vaccine, also known as PSA-TRICOM). Growth rate of tumor if no therapy is initiated (line a). An examination of five clinical trials (four with chemotherapy and one with PSA-TRICOM (PROSTVAC) vaccine) in patients with metastatic prostate cancer demonstrated that with the use of chemotherapy there was an initial tumor reduction, but that the growth rate of tumors at relapse (line b) was similar to the initial tumor growth rate prior to therapy; this is contrasted with the reduction in tumor growth rate following vaccine therapy (line c). Thus, for patients with little or no tumor reduction (and thus virtually no increase in time to progression), an increase in survival was observed. (†) denotes time to death. B, This phenomenon could potentially be enhanced if vaccine therapy is initiated earlier in disease progression or in patients with low tumor burden metastatic disease (line d), but would have minimal effect in patients with large tumor burden (line e). C, Additional therapies received with vaccine may take advantage of both modalities. Adapted from Schlom J. (2012). Therapeutic cancer vaccines: current status and moving forward. J Natl Cancer Inst., Oxford University Press. 104, 599–613.

Fig. 8

Tumor growth rate of a patient with metastatic prostate cancer receiving PSA-TRICOM vaccinations. Prostate-specific antigen (PSA) values (y-axis) are in ng/ml and plotted on the natural log scale; PSA was measured at two different institutions as denoted by the two colors. Time (x-axis) is in years relative to prostatectomy in 1993. The solid black line is a cubic spline smooth. The dashed blue lines are the linear segments fit using segmented linear regression modeling to estimate PSA level doubling time during different periods. XRT, radiation therapy. Adapted from Rojan et al. (2013). Dramatic and prolonged PSA response after retreatment with a PSA vaccine. Clin Genitourin Cancer. 1, 362–364.

Fig. 9

Anti-tumor effects of CEA-TRICOM vaccine in combination with a BCL-2 inhibitor (GX15–070) exploiting the differential effect of the pan BCL-2 inhibitor on Tregs vs. effector cells. Adapted from Schlom et al. Recombinant TRICOM-based therapeutic cancer vaccines: lessons learned (Chapter 20, pp. 309–331). In: Cancer Immunotherapy: Immune Suppression and Tumor Growth, Second Edition. G. Prendergast and E. Jaffee, eds. Elsevier Ltd. (2013).

Fig. 10

Changes in Teff:Tregs ratios and suppressive activity of Tregs during therapy with docetaxel in patients with hormone refractory prostate cancer. A, Waterfall plot of the change in the ratio of Teff:Tregs during therapy with docetaxel in patients with hormone refractory prostate cancer. Peripheral blood samples were collected prior to therapy and before starting cycle II. B, Waterfall plot of the change in suppressive activity of Tregs during therapy with docetaxel. Adapted from Roselli et al. (2013). The effect of nonimmune therapeutic interventions on regulatory T-cell number and function. OncoImmunology. Epub: 11.1.13.

Fig. 11

Changes in Teff:Tregs ratios and suppressive activity of Tregs in non-small cell lung cancer (NSCLC) patients before and during therapy with cisplatin plus vinorelbine. A, Waterfall plot of the change in the ratio of Teff:Tregs in NSCLC patients before and during therapy with cisplatin plus vinorelbine. Patients with NSCLC were treated in the adjuvant setting, post-surgery. PBMCs were collected from peripheral blood at baseline and post-cycle III. B, Waterfall plot of the change in suppressive activity of Tregs from NSCLC patients before and during therapy with cisplatin plus vinorelbine. Adapted from Roselli et al. (2013). The effect of nonimmune therapeutic interventions on regulatory T-cell number and function. OncoImmunology. Epub: 11.1.13

Fig. 12

There was a trend toward improved overall survival in chemotherapy naïve metastatic prostate cancer patients treated with PROSTVAC vaccine and the 10-mg/kg dose of ipilimumab relative to lower dose levels of ipilimumab. Adapted from Madan et al. (2012). Ipilimumab and a poxviral vaccine targeting prostate-specifi c antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol. 13, 501–508.

Fig. 13

Best prostate-specific antigen (PSA) responses after treatment with PROSTVAC vaccine plus ipilimumab. 25% of patients had PSA declines > 50% post-treatment. Adapted from Madan et al. (2012). Ipilimumab and a poxviral vaccine targeting prostate-specifi c antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol. 13, 501–508.

Fig. 14

Brachyury induces epithelial to mesenchymal transition (EMT) in human carcinoma cells. A, Pancreatic carcinoma PANC-1 cells were stably transfected with a control pcDNA or a vector encoding for full length Brachyury (pBrachyury). Top panels: bright field images of cells grown on plastic surface. Bottom panels: immunofluorescence analysis of EMT markers in cells grown on cover glasses. The green signal represents the staining of the corresponding protein, and the blue signal represents the DAPI-stained nuclei. B, In vitro cell migration and ECM invasion assays. Adapted from Fernando et al. (2010). The T-box transcription factor Brachyury promotes epithelial-to-mesenchymal transition in human tumor cells. J Clin Invest. 120, 533–544.

Fig. 15. Brachyury controls tumor dissemination and metastasis.

Athymic mice were inoculated with human H460 lung carcinoma cells transfected as indicated via tail vein. Forty-five days after tumor implantation, animals were euthanized and lungs were evaluated for tumor nodules. Circles denote con.shRNA and triangles denote Br.shRNA. Two representative lungs from each group are shown for comparison. White outlines and black arrowheads point to tumor masses. Adapted from Fernando et al. (2010). The T-box transcription factor Brachyury promotes epithelial-to-mesenchymal transition in human tumor cells. J Clin Invest. 120, 533–544.

Fig. 16

Brachyury as a vaccine target. A, MHC-restricted CTL-mediated lysis of H226 (HLA-A2 negative) and H441 (HLA-A2 positive) lung carcinoma cells with a Brachyury-specific T-cell line. B, Lysis of H441 tumor cells with a Brachyury-specific T-cell line derived from a prostate cancer patient in the presence of cold, competitor K562 A2.1 cells unpulsed or pulsed with the specific Brachyury peptide (Bra pep). C, Lysis of H441 and H1703 lung carcinoma and control ASPC1 cells by tetramer-isolated, CD8⁺ Brachyury-specific T-cell line derived from a different prostate cancer patient. Adapted from Roselli et al. (2012). Brachyury, a driver of the epithelial-mesenchymal transition, is overexpressed in human lung tumors: an opportunity for novel interventions against lung cancer. Clin Cancer Res. 18, 3868–3879.