Lung Cancer Vaccines
Nevin Murray
Robert Eager
John Nemunaitis
Anecdotal observations of spontaneous regression of tumors in patients with cancer provided the initial evidence of the presence of an inborn antitumor immune response. Additionally, the observation of paraneoplastic autoimmunity that can accompany occult malignancies indicates the existence of immunologic activity. Historically, the first reports of therapeutic immune induced tumor regression came over a century ago when William Coley treated cancer patients by nonspecifically activating the immune system with inoculations of live bacterial cultures. However, little progress was made until the 1980s, when Rosenberg et al.1 studied the use of high doses of interleukin 2 (IL-2) in individuals with metastatic kidney cancer or melanoma and achieved objective cancer regressions in 15% to 20% of treated patients.
Classic prophylactic vaccines that have had great success in the prevention of infectious diseases have relied mainly on generation of high titers of neutralizing antibodies. This chapter discusses therapeutic vaccines that elicit an active specific immune response. These vaccines aim at inducing strong antigen-specific T-cell responses. The requirements for therapeutic vaccine development are different and far more complex than those of prophylactic vaccines. The first important issue in vaccine design is that of antigen delivery. Therapeutic vaccines are divided into subunit vaccines or cell-based vaccines (Table 51.1). The subunit vaccine approach is based on the selection of well-defined antigens as targets. The term subunit vaccine may include a gene or gene product, representing part of or an entire polypeptide fragment carrying an antigen recognized by T cells. These include plasmid DNA, messenger RNA, peptides, recombinant proteins, or bacterial/viral vectors carrying gene inserts coding for tumor antigens. Cellular vaccines rely on the approach of using whole tumor cells for vaccination. Either irradiated tumor cells or lysates have been used. Tumor cells may be modified by gene transfer to express cytokines that may enhance their overall immunogenicity.
The focus of most lung cancer vaccines has been the generation of a T-cell response against antigens expressed by tumors. Cancer vaccination is based on the premise that an effective antitumor response can be elicited by the induction of major histocompatibility complex (MHC) class I-restricted cytotoxic T lymphocytes (CTLs), capable of recognizing and lysing tumor cells. Gene-modified tumor vaccines (GMTV) and dendritic cell vaccines (DCV), the two main classes of cellular vaccines investigated in lung cancer, utilize this approach.
GMTV use gene transfer technology to transduce tumor cells with genes encoding cytokines or other immunogenic proteins. DCV utilize antigen modification of autologous dendritic cells (DCs) to elicit a specific T-cell activation against cancer cells. Experimental studies of xenografted animals demonstrated that these vaccines considerably increased the immunogenicity of tumor cells, which, in many cases, induced tumor rejection and regression.1a,2,3,4 Several GMTV platforms have been evaluated for cytokine and gene delivery. These include autologous tumor vaccines, allogeneic tumor vaccines, and bystander vaccines. Autologous tumor cell vaccines involve surgically harvested tumor cells that are genetically modified to increase immune recognition. More commonly, allogeneic vaccines are made up of tumor cell lines that express tumor-associated antigens (TAAs) and are genetically modified to express immunogenic cytokines and proteins. A bystander vaccine is a hybridization of both aforementioned approaches. It utilizes autologous tumor cell antigens, “bystander” cells, in combination with cytokine-secreting allogeneic tumor cells to recruit and activate immune effector cells.
The role of DCs in cell-mediated immunity has been extensively investigated.1a,5,6,7,8 DCs have been found to play a central role in the induction of antitumor immunity in tumorbearing host by a process of antigenic cross-presentation and have displayed activity in non-small cell lung cancer (NSCLC)2 They efficiently display antigens on major histocompatibility complexes (MHC II) ultimately stimulating proliferation and activation of CD4+ and CD8+ T cells. CD4+ cells further augment the activity of natural killer (NK) cells and macrophages, in addition to amplifying antigen-specific immunity by local secretion of cytokines.3,4,9,10,11 These attributes make DCs a central component in therapeutic strategies of many current immune-based therapies in NSCLC.
TABLE 51.1 Approaches to Lung Cancer Vaccines and Immunotherapy | ||||||||||||||||||||||||||||||||||||
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Despite progress made in understanding the molecular biology behind carcinogenesis and advancements in our technical proficiency, clinical application of immune-based cancer vaccines have yielded modest results. There are several hypotheses to explain potential lack of activity, including ineffective priming of tumor-specific T cells, lack of high avidity of primed tumorspecific T cells, and physical or functional disabling of primed tumor-specific T cells by the primary host and or tumor-related mechanism. For example, in NSCLC, a high proportion of the tumor-infiltrating lymphocytes are immunosuppressive T-regulatory cells (CD4+ CD25+) that secrete transforming growth factor β (TFG-β) and express a high level of CTL antigen-4.12,13 These cells have been shown to impede immune activation by facilitating T-cell tolerance to TAAs rather than cross-priming CD8+ T cells, resulting in the nonproliferation of killer T cells that recognize the tumor and will not attack it.12,13,14,15,16,17,18 Elevated levels of IL-10 and TFG-β are found in patients with NSCLC. Animal models have shown immune suppression is mediated by these cytokines serving as a defense for malignant cells against the body’s immune system.19,20,21,22,23,24,25,26,27,28
As our understanding of the pathogenesis of cancer steadily evolves, researchers are continuously developing novel therapies designed to overcome each new challenge. This chapter will discuss recent vaccine therapeutic strategies in lung cancer, focusing on clinical trials that have contributed to our overall understanding of the immune system and its utilization in the treatment of lung cancer.
NON-SMALL CELL LUNG CANCER CELLULAR VACCINES
Lucanix Lucanix is a nonviral gene-based allogeneic vaccine that incorporates the TFG-β 2 antisense gene into a cocktail of four different NSCLC cell lines.29 Elevated levels of TFG-β 2 are linked to immunosupression in cancer patients.30,31,32,33,34,35 Systemic levels of TFG-β are inversely correlated with prognosis in patients with NSCLC.36 TFG-β 2 has an antagonistic effect on NK cells, lymphokine-activated killer cells, and DCs.21,25,26,37,38,39 Using an antisense gene to inhibit TFG-β2, several researchers have demonstrated an inhibition of cellular TFG-β2 expression resulting in an increased immunogenicity of gene-modified cancer cells.40,41,42,43,44,45,46,47,48
In a recent phase II study involving 75 early stage (n = 4) and late stage (n = 61) patients, a dose-related effect of Lucanix was defined. Twenty-nine patients were randomized to one of the three-dose cohorts (1.25 × 107, 2.5 × 107, or 5 × 107 cells/injection × 16 injections). Injections were administered one time each month or every other month until progressive disease criteria were fulfilled. Treatment was well tolerated with only one grade 3 toxic event attributed to the vaccine (arm swelling). A significant survival advantage at dose levels ≥2.5 × 107 cells/injection compared with the low dose level of 1.25 × 107 cells/injection was demonstrated with an estimated 2-year survival of 47% (Tables 51.2 and 51.3). This also compared favorably with the historical 2-year survival rate of <20% of comparable stage IIIB or IV NSCLC patients.49,50,51,52,53,54 Furthermore, a correlation of positive outcome with induction of immune enhancement of tumor antigen recognition was observed. Immune function was explored in the 61 advanced stage IIIB or IV patients. Patients who achieved stable disease or better had increased frequency in the production of cytokines (interferon-γ [INF-γ], p = 0.006; IL-6, p = 0.004; IL-4, p = 0.007) and positive clinical outcomes were correlated with development of human leukocyte antigen (HLA)-antibody response to the vaccine. A total of 11 out of 20 patients with stable disease or better-developed novel HLAantibody reactivity to one or more allotypes of the vaccinating cell lines compared with 2 of 16 progressive disease patients (p = 0.014). It was concluded that further phase III investigation of Lucanix is justified and warranted.
GVAX Lung Given the histological heterogeneity of NSCLC and the relative absence of information on the relevant immunodominant antigens in this disease, in initial trials, autologous tumor cells were selected as the source of tumor antigens in NSCLC.55 The first pilot study of autologous GVAX Lung was conducted by Glenn Dranoff at the Dana-Faber Cancer Institute using a first-generation adenoviral vector and recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF).56 A total of 35 patients underwent tumor harvest and 33 patients received vaccine treatment at three different dose levels. The vaccine was administered weekly for 2 weeks then biweekly until the supply was exhausted. Vaccines were well tolerated with the most common toxicity being local, self-limited vaccine site reactions and mild flulike symptoms in a minority of patients. Antitumor immunity was demonstrated by induction of delayed-type hypersensitivity (DTH) reaction to injections of irradiated, genetically unmodified autologous tumor cells in 82% of patients as well as the presence of inflammatory infiltrates in metastatic tumor biopsies. In addition, one patient demonstrated evidence of tumor regression (mixed response) and two others have remained recurrence
free for more than 5 years following resection of isolated metastatic sites for vaccine preparation.
free for more than 5 years following resection of isolated metastatic sites for vaccine preparation.
TABLE 51.2 Demographics for Recent Vaccine Trials in NSCLC | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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The subsequent study was a multicenter phase I/II trial investigating again an autologous NSCLC tissue vaccine. Manufacturing processes were modified in this trial to enable more rapid commercial development. This study also involved both patients with early and advanced stage disease.57 Patients were enrolled in two cohorts. Cohort A included patients with stage IB or II NSCLC with planned primary surgical resection and no preoperative or postoperative chemotherapy or radiotherapy. Patients in cohort B had surgically nonresectable stage III or IV NSCLC with an accessible tumor to harvest for vaccine processing.
Vaccines were administered subcutaneously every 2 weeks for a total of three to six vaccinations. The vaccine dose was individualized on the basis of yield, and each dose contained 5 × 106 to 10 × 106 cells per vaccination, 10 × 106 to 30 × 106 cells per vaccination, and 30 × 106 to 100 × 106 cells per vaccination (Tables 51.2 and 51.3).
A total of 83 patients underwent tumor harvest (20 in cohort A, 63 in cohort B) and 43 initiated vaccine treatment (10 in cohort A, 33 in cohort B). All 10 patients in cohort A completed vaccine treatment. The median number of vaccines in cohort B was five. The median number of days from tumor harvest to vaccine release was 31 and that from harvest to initiation of vaccine treatment was 49 days. Vaccines were successfully manufactured in 80% of patients in cohort A and 81% of patients in cohort B. The majority of manufacturing failures resulted from an insufficient number of tumor cells.
The most common vaccine-related adverse events were local vaccine injection site reactions (93%); followed by fatigue (16%), nausea (12%), and pain; arthralgia, and upper respiratory infection (each at 5%). Two grade 4 (pericardial effusion) and six grade 3 (dyspnea, fatigue, injection site reaction, hypokalemia, malignant ascites, and pulmonary embolism) possibly related events were reported. There was no association between vaccine dose and the total number of adverse events or grade 3 and 4 adverse events.
Vaccine reaction size (skin induration) was positively associated with level GM-CSF secretion from the transfected autologous malignant cells used as the product. Analysis of vaccine site biopsy specimen showed dense infiltration with CD4+ and CD8+ T cells, CD1a+ DCs, and eosinophils.
Three patients in cohort B achieved durable, complete tumor regressions lasting 6, 18, and 22 months. In addition, there was one minor response (30% decrease in a lung nodule)
and two mixed responses; seven patients had stable disease with a mean duration of 7.7 months. Correlation of dose to survival was demonstrated to be significant at a threshold of 40 ng of GM-CSF per 106 cells per 24 hours expressed from an aliquot of the vaccine prior to the first injection. Long-term follow-up of two of the patients (stage IV refractory disease to prior cytotoxic therapy) achieving complete response reveals continued disease-free survival now more than 5 years after initial GVAX vaccination (unpublished data).
and two mixed responses; seven patients had stable disease with a mean duration of 7.7 months. Correlation of dose to survival was demonstrated to be significant at a threshold of 40 ng of GM-CSF per 106 cells per 24 hours expressed from an aliquot of the vaccine prior to the first injection. Long-term follow-up of two of the patients (stage IV refractory disease to prior cytotoxic therapy) achieving complete response reveals continued disease-free survival now more than 5 years after initial GVAX vaccination (unpublished data).
TABLE 51.3 Results of Recent Vaccine Trials in NSCLC | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Salgia et al.56 also conducted the first phase I trial of GVAX in NSCLC using an autologous vaccine strategy. A total of 37 patients with stage IIB to IV NSCLC were enrolled and 34 vaccines were successfully manufactured at three different dose levels (1 × 106, 4 × 106, 1 × 107 cells). The vaccines were administered weekly for 2 weeks then biweekly until the supply of vaccine was exhausted. Of these patients, 25 received ≥6 vaccinations. Toxicities were limited to grade 1 to 2 erythema and induration at the injection site, as well as fatigue and flulike symptoms (Tables 51.2 and 51.3).
A total of 18 out of 25 patients who received six vaccinations showed significant local reactions. At the vaccination site, these 18 patients showed infiltration of DCs, macrophages,
eosinophils, neutrophils, and lymphocytes. The intensity and frequency of the reaction was related to the dosage administered. Five patients showed stable disease after 33, 19, 12, 10, and 3 months (Tables 51.2 and 51.3). Based on the outcomes of the study, Salgia et al. concluded that GVAX enhances antitumor immunity in some patients with metastatic NSCLC.
eosinophils, neutrophils, and lymphocytes. The intensity and frequency of the reaction was related to the dosage administered. Five patients showed stable disease after 33, 19, 12, 10, and 3 months (Tables 51.2 and 51.3). Based on the outcomes of the study, Salgia et al. concluded that GVAX enhances antitumor immunity in some patients with metastatic NSCLC.
In an effort to remove the requirement for genetic transduction of individual tumors and to optimize GM-CSF transgene expression (given that this correlated with improved survival), a second approach was developed called bystander GVAX, which is a vaccine composed of autologous tumor cells mixed with an allogeneic GM-CSF-secreting cell line (K562 cells)58 and a phase I/II trial of this vaccine in advanced stage NSCLC was conducted. Tumors were harvested from 86 patients, tumor cell processing was successful in 76 patients, and 49 proceeded to vaccination. Serum GM-CSF pharmacokinetics were consistent with secretion of GM-CSF from vaccine cells for ≤4 days, with associated transient leukocytosis confirming the bioactivity of vaccine-secreted GM-CSF. Evidence of vaccine-induced immune activation was demonstrated. However, objective tumor responses were not seen despite a 25-fold higher GMCSF secretion concentration with the bystander GVAX vaccine (Tables 51.2 and 51.3). The frequency of vaccine site reactions, tumor response, time to progression, and survival were all less favorable to autologous GVAX, although results were similar to historical cytotoxic therapy for second-line NSCLC.
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