Healio
Healio
October 05, 2011
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Personalized Vaccine Strategies in Early-stage and Advanced-stage Non–small Cell Lung Cancer

Unlike many approaches to cancer treatment, vaccines are closely tailored to the precise mechanisms by which specific types of tumor cells interact with the immune system. Each vaccine represents a unique approach to the problem of ensuring that a strong immunogenic response is elicited by the non-self proteins contained within the tumor. Because of the safety profile observed in these agents, there is a potential to use them efficiently in combination, so as to simultaneously enhance several different aspects of the interaction between the tumor and immune system.

Development of successful vaccines is based on 3 important principles: to educate the immune system against specific tumor antigens; to stimulate the immune system and improve its ability to effectively target the cancer — in essence, to attempt to break the tolerance that the cancer has been able to evoke in the body; and to block the inhibitors that cancer cells produce to hinder the immune response.

A large number of vaccines, both gene-based and nongene-based, are currently under investigation for use in the treatment of non–small cell lung cancer (NSCLC). This article will examine several novel gene-based vaccines that illustrate the ways in which these principles can be successfully employed to improve the visibility and vulnerability of tumor cells to our immune systems.

Granulocyte-macrophage Colony-stimulating Factor Gene Vaccine (GMCSF)

The GMCSF vaccine (GVAX, Biosante Pharmaceuticals) induces immune activation and exposes tumor antigens. A trial of this approach in prostate cancer, using allogeneic cell lines, was unsuccessful. The technique was modified for use in patients with NSCLC..1 Autologous lung cancer cells harvested from the patients were genetically modified with an adenoviral vector (Ad-GM) to secrete human GMCSF. After irradiation, they were administered intradermally into the patient.

A phase 1/2 trial of GVAX in NSCLC was encouraging.2 Tumors were harvested from 83 patients, 20 with early-stage NSCLC and 63 with advanced-stage NSCLC. Vaccines were successfully manufactured for 67 patients, of whom 43 were vaccinated. Intradermal injections were given every 2 weeks for a total of 3 to 6 vaccinations. The vaccine was well-tolerated; the most common toxicity was a local injection-site reaction (93%). Three of 33 advanced-stage patients who had already failed standard first-line therapy, and 2 of whom had bronchiolo-alveolar carcinoma, had durable complete tumor responses (lasting 6, 18, and 22 months). Many patients treated with the vaccine survived for longer periods than would otherwise have been expected. There appeared to be a vaccine dose-related survival advantage: longer survival was observed in patients receiving vaccines secreting GMCSF at more than 40 ng/24 hour per 106 cells (median survival, 17 months; 95% confidence interval [CI], 6-23) than in patients receiving vaccines secreting less GMCSF (median survival, 7 months; 95% CI, 4-10; P = .028). Assays on a subset of these patients appeared to show a correlation with immune function. However, the majority of patients did not experience durable responses.

Belagenpumatucel-L

Belagenpumatucel-L (Lucanix, NovaRx) blocks the action of transforming growth factor β2 (TGFβ2), a potent immune response inhibitor produced by some lung cancer cells..3 The TGFβ proteins are involved in the growth and regulation of normal cells. However, in cancer, they inhibit a variety of functions that the immune system uses to attack tumor cells, thus protecting the tumor. Elevated levels of TGFβ2 are inversely correlated with prognosis in NSCLC. The actions of TGFβ2 include:

  • inhibition of activation of T cells and B cells;
  • inhibition of the activation of antigen-presenting cells;
  • inhibition of natural killer (NK) cell function;
  • inhibition of γ-interferon production by immune effector cells;
  • induction of FOXP3 expression and the generation of T regulatory cells.

Lucanix is a nonviral gene-based vaccine. This vaccine is synthesized by incorporating a TGFβ2 antisense gene into a pool of allogeneic tumor cells.33 The use of allogeneic cell lines avoids some of the limitations and difficulties of autologous vaccine therapy, including the necessity of harvesting adequate quantities of tumor tissue, difficulties in producing reliable transfection, and long delays between harvesting and vaccine treatment.

A randomized phase 2 trial of Lucanix examined 3 different doses, 1.25 x 107 cells/injection, 2.5 x 107 cells/injection, and 5.0 x 107 cells/injection.4 The dose was administered as an intradermal injection once per month for 4 months, then once a month or every other month for a total of 12 months. Samples were studied for immune function analysis. The majority of the 75 patients in the study had non-resectable stage III or IV disease. An average of 7 vaccinations were administered to each patient. The vaccine was well-tolerated. Of 40 patients with measurable disease, 5 (13%) had a radiographic response. An immune response occurred in many patients, which correlated with lack of disease progression, and there was a dose-related effect on overall survival; patients in the 2 higher dose cohorts had a significantly longer survival time than those on the lower dose (P = .0186; Figure). There was also a correlation between immune response and survival in the study patients. Efforts are continuing to characterize patients who are likely to be more responsive to this vaccine, either initially or during the course of treatment.

Figure. Lucanix: Overall Survival Dose Response

A dose-dependent effect on overall survival was observed in advanced-stage patients receiving 3 different doses of Lucanix.
Dose Cohort 1: 1.25 x 107 cells/injection;
Dose Cohort 2: 2.5 x 107 cells/injection;
Dose Cohort 3: 5 x 107 cells/injection

Source: Nemunaitis J, et al. J Clin Oncol. 2006;24:4721-4730. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.

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Phase 2 data for both GVAX and Lucanix compare favorably with existing second-line chemotherapy or EGF receptor inhibitor therapy in patients with lung cancer, with positive 1-year survival rates and overall survival duration (Table 1).2,4,5-7

Table 1. Therapeutic Options of > 1 Prior Treatment for NSCLC

Key: CR — complete response; GMCSF — granulocyte-macrophage colony-stimulating factor; PR — partial response
Sources: 1. Shepherd FA, et al. N Engl J Med. 2005;353:123-132; 2. Hanna N, et al. J Clin Oncol. 2004;22:1589-1597; 3. Nemunaitis J, et al. J Natl Cancer Inst. 2004;96:326-331; 4. Nemunaitis J, et al. J Clin Oncol. 2006;24:4721-4730; 5. Nemunaitis J, et al. Cancer Gene Ther. 2009;168:620-624.

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A phase 3 trial of Lucanix (STOP) is now recruiting, with 231 of the projected 700 patients accrued as of June 2011.8 The multicenter trial involves 92 sites. Eligibility criteria include stage IIIB/IV NSCLC, with response or stable disease following first-line chemotherapy or chemoradiotherapy. Patients with a response are randomized to Lucanix plus best supportive care or best supportive care alone.

TAG

The successes in activating the immune system and blocking inhibitors with separate vaccines raises the question of whether both effects can be combined in a single vaccine. Although there were initial concerns about overstimulating the immune system, researchers have developed a vaccine that essentially combines the mechanisms employed in GVAX and Lucanix. The TGFβ2 Antisense + rhGMCSF tumor-associated glycoprotein (TAG) vaccine uses an expression plasmid that coexpresses GMCSF and TGFβ2 antisense nucleotide sequences, incorporated into autologous tumor tissue.9,10

The phase 1 trial of TAG recruited 38 patients, of whom 22 were treated. Two of these patients had NSCLC.9 Patients were infused with either 1 x 107 (n = 7) or 2.5 x 107 (n = 15) cells. The median number of vials constructed per patient was 11 (range 7 to 26). Cell viability was 79% to 99% (median 92%). Median GMCSF expression was 394 pg/million cells. Median TGFβ2 knockdown was 54%, and there was minimal TGFβ1 inhibition, as expected. There was little evidence of adverse events, apart from injection site pain.

Stable disease of 3 or more months’ duration was observed in 15 patients, and appeared to be quite prolonged in a follow-up study. One complete response occurred in a patient with stage IVa malignant melanoma, and there was a partial response in another individual, while 2 patients progressed. Three of the patients were not evaluable. Median survival to that time was 465 days, in a population with a life expectancy of between 4 months and 6 months at baseline. Nine patients remained alive as of June 2011, and follow-up continues. There was a correlation in this study between immune response, as determined by ELISPOT results showing activated T-cell expression, and response to TAG. The immune response appeared to increase from day 0. An immune response was not observed in patients who did not demonstrate prolonged survival or stable disease.

To summarize the findings with TAG, no additional toxicity was observed with the combination of the 2 components in 1 vector. This suggests that it may be possible to combine vaccines as well as separate therapeutics in the same patient. There was evidence of anti-tumor activity with this vaccine. The GMCSF expression appeared to be consistent with GVAX, and the TGFβ2 activity was comparable to the Lucanix level of knockdown.

Furin Vaccine

The enzyme furin is responsible for lysing the pro-TGFβ molecule into TGFβ1, β2, and β3..11 Researchers constructed an RNA interference molecule (RNAi) that prevented furin expression in tumor cells, and as a consequence all TGFβs were knocked down to a level of 90% to 95% (Table 2).

Table 2. FANG Vaccine/TAG Vaccine Characterization/Comparison [Mean ± SD] — All Patients

Key: GMCSF — granulocyte-macrophage colony-stimulating factor; TGF — transforming growth factor
Sources: Olivares J, et al. Clin Can Res. 2011;17(1):183-192; Trial of bi-shRNA-furin and granulocyte macrophage colony stimulating factor (GMCSF) augmented autologous tumor cell vaccine for advanced cancer (FANG). http://www.clinicaltrials.gov/ct2/show/NCT01061840. Accessed August 11, 2011.

Click here for a larger view of this figure.

This RNAi was then placed into a vector with GMCSF and used to create adjuvant bi-shRNA furin and GMCSF augmented autologous tumor cell vaccine (FANG, Gradalis, Inc). A phase 1 study was initiated with 45 patients initially involved in this ongoing trial.12 The dosage regimen was 1 x 107 vs. 2.5 x 107 cells/intradermal injection, once per month for 12 months. Results are pending completion of the phase 1 trial.

Summary

The evidence obtained thus far from clinical trials of cancer immunotherapy clearly shows that vaccines vary widely in their effectiveness for individual patients. One of the challenges that researchers face is identifying markers that will predict the susceptibility of a given patient’s tumor cells to the treatment. TG4010 is a novel interleukin (IL)-2, MUC1 gene-based vaccine largely developed in Europe that is entering phase 2/3 lung cancer trials in the United States, focusing on stage IV patients. The activity of this vaccine correlates significantly with the patient’s levels of NK cells, thus NK cell levels appear to pre-identify patients that are more sensitive to the vaccine. A laboratory test is under development to aid in patient selection.

In conclusion, vaccine therapy is already a standard of care in prostate cancer and melanoma. Early studies have demonstrated the safety of this approach in NSCLC, as well as preliminary evidence of efficacy. Vaccination is therefore likely to find a role in the treatment of NSCLC as data from the ongoing phase 2 and 3 trials become available.

References

  1.  Nemunaitis J, Nemunaitis J. Granulocyte-macrophage colony-stimulating factor gene-transfected autologous tumor cell vaccine: Focus on non–small cell lung cancer. Clin Lung Cancer. 2003;5(3):148-157.
  2.  Nemunaitis J, Sterman D, Jablons D, et al. Granulocyte-macrophage colony-stimulating factor gene-modified autologous tumor vaccines in non–small cell lung cancer. J Natl Cancer Inst. 2004;96(4):326-331.
  3.  Thatcher N, Heighway J. Maintenance and consolidation therapy in patients with unresectable stage III/IV non–small cell lung cancer. Oncologist. 2010;15(10):1034-1042.
  4. Nemunaitis J, Dillman RO, Schwarzenberger PO, et al. Phase II study of belagenpumatucel-l, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non–small cell lung cancer. J Clin Oncol. 2006;24(29):4721-4730.
  5.  Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non–small cell lung cancer. N Engl J Med. 2005;353(2):123-132.
  6.  Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non–small cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22(9):1589-1597.
  7.  Nemunaitis J, Nemunaitis M, Senzer N, et al. Phase II trial of belagenpumatucel-L, a TGF-beta2 antisense gene modified allogeneic tumor vaccine in advanced non–small cell lung cancer (NSCLC) patients. Cancer Gene Ther. 2009;16(8):620-624.
  8.  Phase III Lucanix vaccine therapy in advanced non–small cell lung cancer (NSCLC) following front-line chemotherapy (STOP). http://www.clinicaltrials.gov/ct2/show/NCT00676507. Accessed August 11, 2011.
  9.  Olivares J, Kumar P, Yu Y, et al. Phase I trial of TGF-β2 antisense GM-CSF gene-modified autologous tumor cell (TAG) vaccine. Clin Can Res. 2011;17(1):183-192.
  10.  Maples P, Kumar P, Oxendine I, et al. TAG vaccine: Autologous tumor vaccine genetically modified to express GM-CSF and block production of TGFβ2. BioProcess J. 2009;8(1):38-44.
  11.  Maples PB, Kumar P, Yu Y, et al. FANG vaccine: Autologous tumor cell vaccine genetically modified to express GM-CSF and block production of furin. BioProcess J. 2009;8(4):4-14.
  12.  Trial of bi-shRNA-furin and granulocyte macrophage colony stimulating factor (GMCSF) augmented autologous tumor cell vaccine for advanced cancer (FANG). http://www.clinicaltrials.gov/ct2/show/NCT01061840. Accessed August 11, 2011.