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Expert Column



Cancer Vaccines: Is There Reason for Optimism?



Jeffrey S. Weber, MD, PhD



[Medscape Hematology-Oncology 5(1), 2002. © 2002 Medscape, Inc.]







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Introduction



In spite of 20 years of development and great commotion in the lay press about the next cancer vaccine, whose regulatory approval is right around the corner, no cancer vaccine has yet been shown to provide clear patient benefit in a randomized trial and consequently no vaccine for cancer has yet been approved by the US Food and Drug Administration (FDA).



Should the practicing clinician feel that the cancer vaccine field is moribund, with little to offer to patients with metastatic cancer? Or is there reason for optimism? I firmly believe that the latter is true, as shown by several early-generation cancer vaccines like CancerVax and Melacine, which are nearing the conclusion of large randomized phase 3 trials, the outcome of which, if successful, would lead to FDA approval.



In this column, I will discuss new developments in the use of dendritic cells (DCs) and viral vectors as cancer vaccines that hold promise for rapid development, and suggest that patients in a number of clinical settings should be referred by community physicians for investigational vaccine trials.



Early Trials With Tumor Antigen-Pulsed DCs



DCs are nature's sentinels that act to uptake, process, and present antigens to the immune system for recognition by immune T and antibody-producing B cells.[1,2] Rapid developments in DC biology have led to the implementation of clinical trials using DCs derived from peripheral blood mononuclear cells or circulating CD34+ progenitors of cancer patients.



At a recent meeting on "Clinical Developments in Dendritic Cell Therapy" in Pinehurst, North Carolina, researchers from several groups showed that peptide-pulsed and tumor lysate-pulsed DCs could mediate significant clinical effects.Eighteen HLA A*0201(+) patients with metastatic melanoma received subcutaneous injections of CD34+ progenitor-derived autologous DCs pulsed with peptides derived from melanoma antigens MART-1, tyrosinase, MAGE-3, and gp100, as well as influenza matrix peptide and keyhole limpet hemocyanin (KLH) as control antigens, every 2 weeks x 3.[3]



DCs induced an immune response to control antigens (KLH, Flu-MP) in 16 of 18 patients. Regression of > 1 tumor metastasis was observed in 7 of 10 patients without progressive disease. Immune response to melanoma antigens after DC vaccination was associated with a favorable clinical outcome (P = .015).



Nestle first published a trial with intranodally injected DCs in 1998,[4] and updated his series of patients, showing a 25% response rate in metastatic melanoma using DCs pulsed with both peptides and lysates of tumor cells. The presence of vitiligo, a positive prognostic factor in immunotherapy for melanoma, was detected only after treatment with lysate-pulsed DCs, which expressed a diverse but poorly defined repertoire of antigens derived from the whole cell.



Geiger and colleagues[5] conducted a trial of tumor lysate-pulsed immature DCs in children with pediatric malignancies, and found that 4 of 10 patients who completed 3 intradermal vaccinations 2 weeks apart, including those with neuroblastoma, primitive neuroectodermal tumors, and Ewing's sarcoma, had objective responses with 3 complete remissions in chemotherapy-resistant disease.



Fong and colleagues[6] described a trial of a single amino acid-modified carcinoembryonic antigen (CEA) peptide pulsed onto DCs given intravenously. In that trial, advanced colon and lung cancer patients were also treated with Flt3 ligand, a hematopoietic growth factor, resulting in a 20-fold expansion of DCs in vivo. Immunization with these CEA peptide-loaded DCs induced CD8 cytotoxic T lymphocytes that recognized tumor cells expressing endogenous CEA. Staining with peptide-major histocompatibility complex tetramers demonstrated the expansion of CD8 T cells that recognized both the native and altered epitopes and possessed an effector cytotoxic T lymphocyte phenotype (CD45RA+CD27 [-] CCR7 [-] ). After vaccination, 2 of 12 patients experienced dramatic tumor regression, 1 patient had a mixed response, and 2 had stable disease. Clinical response correlated with the expansion of CD8 tetramer-positive T cells, confirming the role of CD8 T cells in this treatment strategy.



Patients with bladder cancer were treated with immature DCs pulsed with a MAGE-3 peptide restricted to HLA-A24, resulting in 2 complete, 1 partial, and 1 mixed response in 4 heavily pretreated patients.[7]



What are we to make of these data of modest clinical import, with many trials showing minor or mixed responses and the occasional dramatic regression? I believe that these early results indicate that our knowledge of how to generate and use antigen-primed DCs has lagged behind our understanding of DC biology and how they are regulated in cancer patients. Antigen-pulsed DCs were a potent antitumor treatment in mouse models, but the complex control of human immunity must be further explored to achieve better results with DC therapy in patients.



Important unanswered questions in this field are how DCs are suppressed in cancer patients, and whether "mature" DCs activated by various inflammatory and T cell-related stimuli are more effective at generating immune cells and clinical responses than "immature" DCs.



A critical experiment in this regard was done by Hartgers and colleagues,[8] who showed an extraordinary autoradiogram of approximately 80% of radioactively labeled mature DC injected intradermally migrating to draining lymph nodes, whereas less than 1% to 2% of immature DCs left the injection site to localize in draining lymph node tissue. This finding, if verified in a larger number of patients, would strongly support the use of mature DCs in future trials. Treatment with DCs remains one of the most attractive and nontoxic ways to immunize patients with cancer, in spite of the fact that clinically significant responses have been few in early trials.





Suppression of DCs and T Cells in Cancer Patients



At a recent Immune Monitoring Workshop at the Society for Biologic Therapy Meeting in Bethesda, Maryland, D. Gabrilovich presented data on DC suppression in cancer patients. He indicated that cytokines produced by tumors such as vascular endothelial growth factor (VEGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte colony-stimulating factor, interleukin (IL)-6, and IL-10 have been implicated in defective DC maturation and impairment of myelopoiesis in tumor-bearing hosts.[9]

Addition of lineage-negative, HLA-DR-positive, immature myeloid cells isolated from the peripheral blood of HLA-A2-positive cancer patients specifically inhibited production of interferon-gamma by CD8+ T cells restimulated with DCs pulsed with the specific peptide. Cancer progression has been associated with increased production of immature myeloid cells as well as immature DCs,[10] and this could be a mechanism by which progressive tumor growth may suppress antigen-specific CD8+ T cell reactivity in tumor-bearing patients.



Overcoming suppression in circulating and tumor infiltrating DCs is a critical step for future development of effective tumor vaccination strategies.





Innovative Vaccines and Ongoing Trials



Several trials of innovative vaccines have recently begun in patients with metastatic and resected colorectal cancer. A fowlpox virus construct encoding both the CEA protein and an immune-stimulating molecule called B7.1 has been developed and has been added to 5-fluorouracil/leucovorin/CPT-11 therapy in patients with metastatic colorectal cancer.



In a phase 2 pilot trial, patients randomly receive the vaccine before and during chemotherapy (with or without tetanus toxoid as a "boost") or they received the vaccine only after response to chemotherapy. The fowlpox virus is used instead of a vaccinia virus vector to avoid the strong antivaccinia response that would be observed in subjects born before the 1950s who have received a smallpox vaccine. This 100-patient pilot trial is powered to detect changes in immune response and time to progression.



The trial is based on recently published data[11,12] indicating that a fowlpox vaccine encoding CEA and B7.1 used to treat 39 patients with metastatic CEA-expressing carcinomas resulted in disease stabilization in 8 of 31 patients and decrease in serum CEA in 8, who had a pretreatment elevation. In a subsequent trial by the same group, 30 patients with metastatic CEA-expressing carcinomas received GM-CSF plus the fowlpox vaccine. CEA-specific immunity was decreased compared with the previous 30 patients who received vaccine alone.



In both trials, the number of prior chemotherapy regimens was negatively correlated with immune response, whereas there was a positive correlation between the number of months from the last chemotherapy regimen and immune response. Of 25 evaluable patients receiving vaccine alone, 11 were stable, but of the 22 who received vaccine/GM-CSF, only 6 were stable and received further vaccine injections. No objective responses were seen.



The strategy employed by the group developing the CEA fowlpox virus has strengths in that they are adding immune manipulation to an effective chemotherapy regimen and asking whether a pharmacodynamic end point (immune response) is affected. Some information on time to relapse and overall survival will be obtained in this small (34 patients per arm) trial to evaluate clinical benefit.



Conclusions



Ultimately, vaccine development should take place in the adjuvant setting (eg, in patients with minimal residual disease in which a vaccine strategy is far more likely to exert a cytostatic effect and be effective in controlling microscopic disease than mediating regression of bulk disease).



This was also a consensus reached at the recent Immune Monitoring Workshop, in which the participants agreed that future cancer vaccine trials should be directed to the treatment of patients after surgical resection of disease but at high risk of relapse. A number of such pilot trials are now under way, and will likely encourage the performance of future large randomized adjuvant trials with peptide, DNA plasmid, or DC-based strategies.