Abstract
Currently, the backbone of therapy for metastatic disease is cytotoxic chemotherapy, along with the recent addition of targeted therapy based on molecular markers with KRAS testing. Despite the improvement in survival for metastatic colon cancer, newer agents are still needed. The clinical activity of TroVax in metastatic colon cancer has been studied in a small number of clinical trials. There is evidence that supports the vaccine's ability to induce humoral and cellular responses, as demonstrated by positive 5T4 and MVA-specific antibody titers and cellular proliferation assays. Future strategies should focus on investigating the immunomodulatory effects of chemotherapy in conjunction with TroVax, understanding the optimal dosing and schedule of the combination, and examining potential predictive biomarkers to determine which patients may benefit from immunotherapy from those who do not.
Abbreviations
| ADCC | = | Antibody-dependent cell-mediated cytotoxicity |
| CEA | = | Carcinoembryonic antigen |
| CRC | = | Colorectal cancer |
| DT | = | Doubling time |
| EBNA-1 | = | Epstein Barr-Virus nuclear antigen-1 |
| EGFR | = | Epidermal growth factor receptor |
| HRPC | = | Hormone refractory prostate cancer |
| IHC | = | Immunohistochemoical |
| ITT | = | Intention to treat |
| LMP-2 | = | Latent membrane protein-2 antigens |
| mCRC | = | Metastatic colon cancer |
| mRCC | = | Metastatic renal cell carcinoma |
| MSKCC | = | Memorial Sloan-Kettering Cancer Center |
| MVAs | = | Modified vaccinia Ankara |
| NSCLC | = | Non-small cell lung cancer |
| OS | = | Overall survival |
| PD-1 | = | Programmed death 1 receptor |
| PD-L1 | = | Programmed-death ligand 1 |
| PFS | = | Progression free survival |
| PMNs | = | Peripheral blood mononuclear cells |
| RCC | = | Renal cell carcinoma |
| TAAs | = | Tumor-associated antigens |
| T-FOLFOX | = | Trovax and FOLFOX |
| T-FOLFIRI | = | Trovax and FOLFIRI |
| TILs | = | Tumor-infiltrating lymphocytes |
| TTP | = | Time to progression |
| VEGF | = | Vascular-endothelial growth factor |
Introduction
Colorectal cancer (CRC) is the fourth leading cause of cancer in the United States. In 2013, an estimated 143,000 new cases were diagnosed and 51,000 deaths were reported. Twenty percent of patients with colorectal cancer had metastatic disease at initial diagnosis. The 5-year survival for patients with metastatic colorectal cancer (mCRC) is 12.5%, which is dramatically inferior to the 5-year survival rates for patients with early, non-metastatic colon cancer, 70.4% with local-regional spread and 90.3% for those with localized disease, respectively.Citation1 The median survival of metastatic cancer has improved beyond 12 months over the past 60 yCitation2 With the increasing availability of novel agents targeting vascular-endothelial growth factor (VEGF), such as bevacizumab and aflibercept, and epidermal growth factor receptor (EGFR) -directed therapy with cetuximab and panitumumab, the overall median survival of metastatic colorectal cancer has increased to 21–26 months. Notably, a subset of mCRC patients with resectable hepatic or pulmonary metastases can have 5-year survival rates ranging from 36% to 60%.Citation3,4 The use of “modern” neoadjuvant chemotherapy for downstaging unresectable disease and more aggressive metastatectomies has resulted in improved long-term survival.Citation2,5 However, recurrence of metastatic disease occurs in almost 2 thirds of these patients.Citation4 Currently, the backbone of standard of care for metastatic disease is cytotoxic chemotherapy, along with the recent addition of targeted therapy based on molecular markers with KRAS testing.
Despite the improvement in survival for metastatic colon cancer, newer agents are still needed. Development of vaccine therapies and immunotherapeutic drugs such as Sipuleucel-T,Citation6 GP-100, and ipilimumabCitation7,8 and their impact on outcomes for metastatic castrate-resistant prostate cancer and malignant melanoma, respectively, has paved the way for other future therapies. Current immunotherapeutic drugs are under investigation in early-phase studies, including GP96 heat shock-protein peptide complex in malignant gliomasCitation9,10 and Reolysin in advanced solid tumors.Citation11 Improved understanding of cancer immunotherapy has led to the development of agents directed at the tumor microenvironment and immune checkpoint signaling involving the programmed-death 1 (PD-1) receptor and its ligands, PD-L1 and PD-L2.Citation12,13 Viral vector-based vaccine therapy is being more commonly evaluated for cancer therapies due to its well-documented safety profile and proven ability to generate potent immune responses. This therapy involves identifying tumor-associated antigens (TAAs) that are typically expressed in high levels on the surface of malignancies.Citation14,15
The Vaccine
TroVax is a highly attenuated strain of vaccinia virus, modified vaccinia Ankara (MVA), encoding the human oncofetal antigen 5T4. The 5T4 antigen is a 72-kDa transmembrane glycoprotein with an extracellular part composed of leucine-rich repeat domains separated by hydrophilic amino acids with 7 N-linked glycosylation sites. The 5T4 antigens are rarely detected on normal tissues and are expressed at high levels on trophoblastic cells and most adenocarcinomas, including colorectal, breast, kidney, bladder, prostate, gastric, and ovarian cancer. The gastrointestinal tract, breast, kidney, and ovaries demonstrate the highest levels of 5T4 expression (>80 %).Citation15,16 Notably, tumor expression of 5T4 is thought be associated with metastatic potential. Also, it has been established that increasing levels of 5T4 expression coincide with increasing tumor stage and that overexpression is associated with poor prognosis.Citation15–17 The membrane-bound 5T4 antigen can initiate antibody-dependent cell-mediated cytotoxicity (ADCC) as well as cytotoxic T cell responses.Citation16
MVA is a double-stranded DNA virus with a linear genome that can infect mammalian cells and is able to accept large inserts of foreign DNA and express transgenes in target cells, including dendritic cells. Viral replication and transcription occurs solely in the cytoplasm of host cell, thus precluding insertional mutagenesis. The construction of this attenuated vaccinia virus includes deletion of certain pathogenic genes, resulting in its inability to replicate infective viral particles and complete its life cycle. Therefore, the MVA is highly immunogenic, resulting in host neutralizing antibodies after one to 2 immunizations.Citation15 In TroVax, expression of the transgene, 5T4, by the MVA vector, induces a potent cellular immune response, which has been demonstrated in recent trials.Citation14-19
MVA-vectored vaccines are being explored in other malignancies. TG4010 is an MVA-vectored vaccine that expresses recombinant MUC-1 and IL-2 transgenes and has been tested in patients with metastatic renal cell carcinoma (mRCC), prostate cancer, and non-small cell lung cancer (NSCLC).Citation20-22 There were no objective clinical responses in the 37 metastatic RCC patients who received TG4010 in combination with cytokines as first-line therapy. Immune response analysis included anti-MVA and anti-IL2 antibodies, CD4+ T-cell response, and MUC1- specific CD8 T+ cell response. Patients with MUC1-specific CD8+ T cell responses were associated with longer survival compared to the overall population.Citation20 Among the 40 patients with biochemical failure prostate cancer, PSA doubling time (DT) was nearly twice as long in 13 patients and PSA stabilization occurred in 10 patients. Similar to findings in metastatic RCC, patients who had stronger MUC1-specific responses experienced greater than median improvement in PSA DT.Citation21 In the phase 2 trial of TG4010 in NSCLC patients, patients were randomized to 2 arms: Arm 1: vaccine and chemotherapy including cisplatin and vinorelbine versus Arm 2: vaccine alone until disease progression followed by vaccine and chemotherapy. The median survival of Arm 1 was 12.7 months vs. Arm 2 was 14.9 months. As with the other 2 trials, the MUC1-specific response was associated significantly longer time to progression and overall survival.Citation22 Ongoing early phase trials are investigating the use of MVA-vectored vaccines include a phase Ib trial in patients with nasopharyngeal carcinoma with the vector encoding the Epstein Barr Virus nuclear antigen-1 (EBNA1) and latent membrane protein-2 antigens (LMP-2)Citation23 and a phase I trial of MVA Brachyury-TRICOM in advanced carcinomas.Citation24
Clinical Trials in Metastatic Colon Cancer
The clinical activity of TroVax in metastatic colon cancer has been studied in a small number of clinical trials. In an open-label phase I/II TroVax trial of 22 patients with mCRC, patients were assigned to 4 groups, starting at the lowest vaccine dose, group 1 (5 × 107 plaque-forming units [PFU]) to group 4 (1 × 108 PFU). The vaccines were administered on weeks 0, 4, and 8. All patients received at least ≥3 vaccinations; 5 patients withdrew and were not considered evaluable. The remaining 17 patients demonstrated an evaluable immune response and had received ≥ 3 vaccinations. This population consisted of mCRC patients who had responded or had disease stabilization on first-line chemotherapy and were assigned sequentially to 4 groups starting at the lowest vaccine dose. The vaccinations were either given intramuscularly (n = 16) or intra-dermally (n = 6) and were well tolerated. The most commonly reported adverse event being local injection site reactions. Measurements of the humoral and 95 cellular responses were obtained by monitoring the 5T4- and MVA-specific antibody titers and proliferation assays on fresh peripheral blood mononuclear cells (PMNs), respectively. Fourteen patients showed detectable 5T4-specific antibody titers after ≥2 vaccinations, whereas a positive MVA-specific antibody response largely occurred after 1 vaccination with titers ranging from 4,000 to 128,000. Eight patients demonstrated de novo 5T4- specific proliferative responses with mean time of positive 5T4 proliferative response of 7.2 weeks. However, 6 patients failed to show proliferative responses. Of the 22 patients, 5 patients demonstrated stable disease ranging from 3 to 18 months. The 5T4- and MVA-specific antibody responses were evaluated as surrogate predictors of time to progression (TTP) and overall survival (OS) through determination of the mean antibody titers detected within the first 12 weeks after immunization (i.e., the sum of antibody titers detected as weeks 2, 4, 6, 8, 10, and 12 divided by 6). There was a statistically significant association with 5T4 antibody levels in all-evaluable patients with time to progression (P < 0.01) and a stronger relationship when analyzing only the subset of patients who mounted 5T4 responses (P < 0.0001). The magnitude of 5T4 response was a predictor of improved OS in 5T4 antibody responders (P < 0.05).Citation17
An open-label phase II trial evaluated TroVax in 20 metastatic colorectal cancer patients with resectable liver metastases with one patient later found to be incorrectly diagnosed with metastatic CRC. Two vaccinations were given at 4 and 2 weeks preoperatively, and 2 subsequent vaccinations were given after the planned surgical resection at 4 and 8 weeks. For patients who demonstrated 5T4-specific immune responses, 2 additional vaccinations were given post-operatively at 20 and 28 weeks. Eighteen of the 19 evaluable patients showed positive 5T4-specific antibody responses after TroVax vaccination with titers ranging from 40 to 2,560. Similarly, all 19 patients demonstrated a robust MVA-specific antibody response with titers ranging from 4,000 to 128,000. Proliferative responses to TroVax were found in 13 of the 20 intention to treat (ITT) patients.Citation4 Biopsies were obtained from liver metastases and adjacent healthy liver tissue for isolation of tumor-infiltrating lymphocytes (TILs) from 19 patients, 17 of which had evidence of 5T4 expression in the tumor samples. The 2 remaining samples were poorly preserved and unable to be assessed. Notably, the pattern of 5T4 expression was predominantly stromal in 10 specimens and a mixed pattern of both tumor and stromal 5T4 expression in the other 7 specimens. Immunohistochemical (IHC) analysis on the resected tumor biopsies showed that the infiltration of T cells/mm3 was higher in the peritumoral regions, whereas there were only small numbers in distant surrounding liver tissue (CD3: 237+/−48, CD4:CD8 ratio: 3.5:1). Survival analysis for these patients was stratified into those who were “above” or “below” the median serologic, proliferative, or infiltrating lymphocyte levels. Immunologic responses that were considered “above” the median if there were at least ≥2 time points in which the immunologic response was above the median from the start of vaccination to 14 weeks. Conversely, “below” the median was defined to be no response above the median from the start of vaccination to 14 weeks. Patients with above the median 5T4 antibody and proliferative responses and CD3+ T-cell infiltration of the colon cancer metastases had significantly longer survival (log-rank, P = 0.047).Citation4,16 Also, higher peritumoral CD3 infiltration was also significantly associated with prolonged survival (P = 0.012).Citation4
Two subsequent studies evaluated TroVax in combination with 2 common regimens used in CRC in first line: 5-fluorouracil (5FU), folinic acid, and oxaliplatin (FOLFOX); and 5-fluorouracil, folinic acid, and irinotecan (FOLFIRI).Citation18,19 5T4-specific antibody and cellular responses were demonstrated in each regimen. There were 11 of 17 evaluable metastatic CRC patients who were given TroVax in combination with FOLFOX chemotherapy (T-FOLFOX) and 12 of 19 evaluable patients with FOLFIRI (T-FOLFIRI). The schema for both trials included administration of a total of 6 vaccinations, with 2 injections each before, during, and following chemotherapy for all patients.Citation18,19 After 2 or more vaccinations, 10 patients who had received T-FOLFOX showed 5T4-specific antibody titers ranging from 10 to 1,280. MVA-specific antibody responses with all patients demonstrated de-novo responses ranging from 2,000 to 512,000. During chemotherapy, the median MVA antibody titer was 22,291; after chemotherapy, the median titer increased to 46,545.Citation18
Carcinoembryonic antigen (CEA), a highly specific tumor marker for CRC, is used for monitoring response to therapy in mCRC as well as detecting asymptomatic recurrence and potentially resectable disease. An elevated CEA prior to surgical resection has been correlated with adverse prognosis and useful for postoperative surveillance.Citation25,26 In the studies, CEA levels were obtained at baseline, during and after completion of chemotherapy. Of the 11 patients who had elevated baseline CEA levels (>5 μg/L), 7 showed >50 % reduction at ≥1 time point throughout the trial. The 5T4 cellular responses correlated to clinical response as indicated by RECIST response score (P = 0.006) and change in tumor burden (P = 0.035). Radiological responses were observed in 5 (45%) of 11 patients at week 14 (6 cycles of chemotherapy and 3 TroVax vaccinations). Six of the 11 evaluable patients had complete or partial responses (1 CR, 5 PR) between weeks 28 and 37 based on radiological studies. Median survival was 68 weeks in the 17 intent-to-treat (ITT) patients and 118 weeks in the 11 evaluable patients, respectively.Citation18
Similarly, for patients who received T-FOLFIRI, 10 of 12 patients had 5T4-specific antibody titers ranging from 10 to 5,120 after at least 2 vaccinations. The mean 5T4 antibody titers increased significantly after chemotherapy in 10 of the patients, from 4.5 during chemotherapy to 163.3 after completion of chemotherapy (P < 0.01). MVA-specific antibody responses were positive after a single vaccination in most of the patients. INF-γ ELISPOT responses specific to 5T4 peptide occurred in 10 patients after TroVax vaccination. Analysis of cellular kinetics of one patient showed that 5T4-specific responses increased after administration of TroVax and chemotherapy. The 5T4 responses remained positive at 40 weeks after administration of the first dose of TroVax. Of the 12 patients with baseline elevated CEA, 50% showed a decrease of CEA. Clinical responses included one CR and 6 PR, and median survival was 18.6 months in the 12 evaluable patients compared with 15.4 months in the 19 ITT patients.Citation19
Discussion
Despite the limited number of clinical trials investigating TroVax in metastatic colon cancer, the data supports the vaccine's ability to induce humoral and cellular responses, as demonstrated by positive 5T4- and MVA-specific antibody titers and cellular proliferation assays. The immune function and dysregulation of T cells and dendritic cells in cancer patients has been well described.Citation27,28 Yet, this initial phase I study in CRC by Harrop et al.Citation17 has established that TroVax could stimulate humoral and cellular responses in a heavily pre-treated patient population with metastatic disease.
For effective oncolytic therapy development, several approaches are used to shield the host's immune response from making neutralizing antibodies to the vector, which can impair the vaccine activity.Citation15,28 TroVax produces a strong MVA-specific immune response with little detrimental effect on 5T4-specific response, as supported by trial results. The strong immunogenic response elicited by the MVA vector produces host-neutralizing antibodies upon initial immunization for nearly all patients. Despite this potent response to MVA as showed by the high MVA-specific antibody titers, the host's immune system was able to produce 5T4-specific antibodies after 2 or more immunizations, suggesting more than one injection is need to break self-tolerance. In the initial phase I/II trial, 5T4-specific cellular and humoral responses occurred after 2 or 3 TroVax vaccinations despite high levels of MVA neutralizing antibodies after the initial vaccinations.Citation17 In addition, the 5T4 immune responses of patients receiving chemotherapy with TroVax were boosted after each vaccination when compared to titers measured on the day of vaccination. Unlike the MVA responses in FOLFOX and TroVax, the responses were diminished among patients treated with FOLFIRI and TroVax. However, in both trials, the magnitude and MVA responses did not correlate with clinical benefit.Citation18,19
The trials collectively concluded that the magnitude of 5T4 antibody responses correlate with therapeutic benefit. In the initial open phase I/II in mCRC patients, the magnitude of 5T4 response was a predictor of improved OS in 5T4 antibody responders in the evaluable patients.Citation17 In the subsequent phase II trial of 20 mCRC patients with resectable liver metastases, the patients with greater 5T4 antibody and proliferative responses also experienced significantly longer survival.Citation4,16 In the 2 trials evaluating the combination of chemotherapy with TroVax, 6 of the 11 patients in the FOLFOX/TroVax trial achieved an objective complete or partial response; in the FOLFIRI/TroVax trial, 1 patient had a CR, 6 had a PR, and 5 had SD. The clinical response as indicated by RECIST response score and change in tumor burden correlated to the 5T4 cellular response. Similarly, clinical benefit as demonstrated by 5T4 cellular responses have been demonstrated in the 3 phase II trials of metastatic renal cell carcinoma (RCC) patients who received TroVax in combination with IFN-αCitation29,30 with IL-2.Citation31,32 The median progression free survival (PFS) across these trials among patients who mounted 5T4 cellular responses was increased compared to those who did not mount responses.Citation29-32 Similarly, TroVax alone versus TroVax in combination with GM-CSF was investigated in hormone refractory prostate cancer (HRPC) and demonstrated a slight improvement in time to disease progression among patients who developed 5T4-specific T cell responses, although no objective clinical responses were observed in the study.Citation33 Contrastingly, there was no correlation between survival and magnitude of MVA-specific responses among these trials.Citation16-19,Citation29-33 Future trials may consider investigating the 5T4 cellular response as a parameter for clinical response and could potentially identify subgroups of patients who may benefit from TroVax.
The median overall survival of mCRC is around 21–26 months with current first-line treatments with FOLFOX or FOLFIRI, often in combination with biologic-targeted therapy. Interestingly, though a small cohort of patients, the addition of TroVax to first-line therapy with FOLFOX demonstrated a median survival of 27 months,Citation18 which should be further evaluated and developed in future trials. Also, TroVax was very well tolerated among the patients, with minimal adverse events other than local injection site reactions. There was no serious grade 3–4 adverse effects related to TroVax, even in combination with chemotherapy.
There is an ongoing open-label phase II study in the United Kingdom examining the immunological activity of TroVax in combination with low doses of cyclophosphamide in inoperable metastatic CRC.Citation34 It has been established that low-dose cyclophosphamide possesses immunomodulatory effects that can augment immune responses by decreasing the number and functionality of regulatory T cells.Citation35 This trial underscores that the relationship between immunotherapy and chemotherapy is still not well described. The 5T4-specific antibody response was induced after 2 or more vaccinations, whereas one initial vaccination of TroVax was able to induce the MVA-specific antibody response. Thus, the duration of the immune responses remains unknown and may be transient, proposing the possibility of alternative schedules of accelerated vaccination or booster immunizations. The trials of TroVax with chemotherapy have demonstrated the feasibility of the combination and provide support that chemotherapy could augment vaccine therapy. The trials in which objective responses were achieved (T-FOLFOX: 1CR, 5PR, T-FOLFIRI: 1CR, 6PR) also highlight the clinical activity of TroVax and chemotherapy.Citation18,19 5T4 and MVA-specific antibody titers were incrementally higher in the patients treated with chemotherapy compared to the initial phase I trial, in which the patients were treated with TroVax alone. The significance of this is unknown and should be elucidated. However, it is not appropriate to comment or make generalizations across trials. Chemotherapy-induced apoptosis resulting in antigen loading may make immunotherapy more effective. This underscores the need to explore optimal timing and sequencing of immunotherapy and chemotherapy.
Interestingly, clinical benefit was derived in metastatic renal cell carcinoma patients who were treated with TroVax in combination with IL-2 and were considered to have a good prognosis according to Memorial Sloan-Kettering Cancer Center (MSKCC) guidelines. The efficacy of the vaccine was affected by normal baseline levels of platelets, monocytes, and hemoglobin.Citation14,15 Based on the existing data, the magnitude of 5T4-specific antibody response and CD3+ T cell infiltration of the colon cancer metastases determined by IHC analysis were associated with improved survival. This highlights the limited understanding of immunotherapy and the lack of predictive biomarkers to stratify patients who may benefit vs. those who will not.
The existing results support the ability of TroVax to induce immune responses within the host; however, the mechanism by which it acts within the tumor and stromal environment is not well described. The pattern of expression of 5T4 included tumor and stromal or predominantly stromal expression in the patients who received TroVax. It would be helpful to obtain the baseline 5T4 expression of the tumor prior to TroVax administration and analyze the changes that may occur with the tumor after exposure to the vaccine. Similarly, the changes in CD3+ T cell infiltration in colon cancer metastases should be evaluated before and after immunotherapy to determine how the T cells may manipulate the tumor and stromal microenvironment. Future strategies should focus on investigating the immunomodulatory effects of chemotherapy in conjunction with TroVax, understanding the optimal dosing and schedule of the combination, and examining potential predictive biomarkers to determine which patients may benefit from immunotherapy from those who do not.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Acknowledgements
We would like to acknowledge our scientific editor, Virginia Mohlere.
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