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PubMed1997

Cellular cancer vaccine induces delayed-type hypersensitivity reaction and augments antibody response to tumor-associated carbohydrate antigens (sialyl Le(a), sialyl Le(x), GD3 and GM2) better than soluble lysate cancer vaccine.

Allogenic whole cell and lysate cancer vaccines are associated with very different clinical outcome, which could be due to different immune responses to critical tumor-associated antigens. We used a guinea pig model to evaluate the immune responses to melanoma-associated carbohydrate antigens administered in whole cell and soluble lysate vaccines produced from the same cell lines and administered with or without Bacille Calmette-Guerin (BCG). Animals immunized with whole cell vaccine developed a significantly higher delayed-type hypersensitivity (DTH) reaction. The IgG response to all tumor-associated carbohydrate antigens except GD2 was significantly higher in animals immunized with whole cell vaccine than lysate vaccine. This study indicates that whole cell vaccine is superior to soluble or lysate vaccine because it induces a better immune response against cell-surface antigens. The addition of BCG significantly increased the antibody response, suggesting that an exogenous adjuvant may immunopotentiate antigens better in the presence of an intact cell membrane.

Adjuvants, Immunologic↗
PubMed2005

Development of an interferon-based cancer vaccine protocol: application to several types of murine cancers.

A protocol for the development of cancer vaccines is presented. The protocol is based upon the long-term in vitro treatment of cancer cells with interferon (IFN)-alpha to create cancer vaccine cells. This protocol has been used to develop cancer vaccines in mice against B16 melanoma, RM-1 prostate cancer, and P388 lymphocytic leukemia. A detailed description of the protocol is presented. Important considerations that are discussed include the method of selection of potential cancer vaccine cells that would make good models for cancer vaccines for human cancers, the effects of in vitro IFN-alpha treatment concentration on the efficacy of generated cancer vaccine cells, the differential ability of cancer cells to become efficacious cancer vaccine cells in response to IFN-alpha treatment, the determination of the effectiveness of ultraviolet-light killing of various cancer cell types for generating cancer vaccine cells, and the methods of evaluation of statistical significance of the data obtained. Potential problems also are addressed.

Animals↗
PubMed2006

Development of WT1 peptide cancer vaccine against hematopoietic malignancies and solid cancers.

Wild-type Wilms' tumor gene WT1 is highly expressed not only in hematopoietic malignancies, including leukemia and myelodysplastic syndromes (MDS), but also in various kinds of solid tumors. Human cytotoxic T lymphocytes (CTLs) which could specifically lyse WT1-expressing tumor cells with HLA class I restriction were generated in vitro. We have also demonstrated that mice immunized with the WT1 peptide or WT1 cDNA rejected challenges by WT1-expressing tumor cells and survived with no signs of auto-aggression to normal organs which physiologically expressed WT1 in prophylactic and therapeutic models. Furthermore, we and others detected IgM and IgG WT1 antibodies in the patients with hematopoietic malignancies, indicating that WT1 protein was highly immunogenic, and that immunoglobulin class-switch-inducing WT1-specific cellular immune responses were elicited in the patients. CD8+ WT1-specific CTLs were also detected in peripheral blood or tumor-draining lymph nodes of cancer patients. These results provided us with the rationale for elicitation of CTL responses targeting the WT1 product for cancer immunotherapy. On the basis of the findings mentioned above, we performed a phase I clinical trial of WT1 peptide cancer vaccine for the patients with malignant neoplasms. These results strongly suggested that WT1 peptide cancer vaccine had efficacy in the clinical setting, because clinical responses, including reduction of leukemic blast cells or regression of tumor masses, were observed after the WT1 vaccination in patients with hematopoietic malignancies or solid cancers. The power of TAA-derived cancer vaccine may be enhanced by combination with stronger adjuvants, helper peptide, or conventional treatments such as molecular-target-based drugs.

Animals↗
PubMed2006

Recombinant viral vectors: cancer vaccines.

To date cancer vaccines have yet to show efficacy in a phase III trial. However, the clinical benefit seen with monoclonal antibody mediated therapies (e.g., Herceptin) has provided proof of principle that immune responses directed against tumour-associated antigens could have therapeutic potential. The failure of past cancer vaccine trials is likely due to several factors including the inappropriate choice of tumour antigen, use of an unoptimised antigen delivery system or vaccination schedule or selection of the wrong patient group. Any one of these variables could potentially result in the induction of an immune response of insufficient magnitude to deliver clinical benefit. Live recombinant viral vaccines have been used in the development of cancer immunotherapy approaches for the past 10 years. Though such vectors are self-adjuvanted and offer the ability to express multiple tumour-associated antigens (TAAs) along with an array of immune co-factors, arguably, they have yet to demonstrate convincing efficacy in pivotal clinical trials. However, in recent years, more coordinated studies have revealed mechanisms to optimise current vectors and have lead to the development of new advantageous vector systems. In this review, we highlight that live recombinant viral vectors provide a versatile and effective antigen delivery system and describe the optimal properties of an effective viral vector. Additionally, we discuss the advantages and disadvantages of the panel of recombinant viral systems currently available to cancer vaccinologists and how they can work in synergy in heterologous prime boost protocols and with other treatment modalities.

Animals↗
PubMed2006

Recent advances in heat shock protein-based cancer vaccines.

BACKGROUND: Active immunotherapy has been successful in preventing many infectious diseases, and is being explored for its anti-tumor use. Purified antigens, peptides, gene-based systems and antigens contained in whole cells or cell lysates are used in specific active immunotherapy for cancer, known as cancer vaccines. Cancer vaccines do not directly kill tumor cells, but prime a specific humoral and/or cellular immune response against the tumor. Up to date, many kinds of cancer vaccines have been tested in the world and have shown their own advantages. Heat shock protein (HSP)-based cancer vaccine is one of the outstanding representatives. In this paper, we review recent advances in HSP-based cancer vaccines. DATA SOURCES: An English-language literature search was conducted using MEDLINE (1990-2005) on HSP, cancer vaccines and other related subjects. RESULTS: Several kinds of HSP-based cancer vaccines which have been explored worldwide, include tumor derived HSP-peptide complex cancer vaccines, artificially reconstituted HSP-peptide complex cancer vaccines, HSP-peptide fusion protein cancer vaccines and HSP-based DNA cancer vaccines, etc. Many HSP-based cancer vaccines are being tested in clinical trials, and some are being tested in phase III clinical trials at present. CONCLUSION: The available results in preclinical tests and clinical trials indicate that HSP-based cancer vaccines are promising in cancer therapy.

Animals↗
PubMed1999

Advances in cancer vaccine development.

Traditionally, cancer vaccines have used whole tumour cells administered in adjuvant or infected with viruses to increase the immunogenicity of the cells. With the identification of tumour-associated and tumour-specific antigens (TAA, TSA), antigen and epitope-specific vaccines have been designed. Compared to tumour cell vaccines, antigen and epitope vaccines are more specific and easier to produce in large quantities but may display lower immunogenicity and lead to the in vivo selection of antigen or epitope-negative escape tumour variant cells. The optimal vaccine will elicit both humoral and cellular immunity in the patients as both parameters have been positively correlated with the induction of beneficial clinical responses. The choice of adjuvant, costimulation and delivery mode greatly determines the outcome of vaccinations and may favour the induction of T-cell responses of T helper (Th)1, Th2, or both Th1 and Th2 types. Animal models of TAA vaccines must take into account the normal tissue expression of TAA, which may induce immunological tolerance to TAA. With the identification of homologues of human TAA in animals, novel experimental models of cancer vaccines which mimic the condition in patients are now available. Several vaccines comprising tumour cells, TAA or anti-idiotypic antibodies mimicking TAA have recently entered phase III of clinical evaluation.

Animals↗
PubMedDate not supplied

Cancer vaccines. Part 2.

Cancer vaccines are being widely studied for the purpose of immune modulation and subsequent antitumor effects. This article cites only a few examples of the many studies underway. Many vaccines have shown efficacy in eliciting systemic responses with minimal toxicities. The use of vaccines as a modality of cancer therapy in combination with chemotherapy, surgery, and radiation therapy is also being investigated. Although the routine use of approved vaccines is still a goal for the future, instituting this fourth modality of cancer therapy is not too distant. Phase III trials with both melanoma and colon cancer vaccines have been completed. Synthetic carbohydrate antigen vaccines have shown efficacy in several tumor types during Phase II trials and are also generating enthusiasm. The potential impact of vaccine therapy on the profession of pharmacy may involve patient counseling regarding management of side effects and possibly also dispensing of vaccine therapy products to patients directly for home administration. As ambulatory sites open in conjunction with pharmacy services and pharmacists obtain prescribing authority, pharmacists' active involvement in vaccine counseling and administration seems likely.

Cancer Vaccines↗
PubMed1996

Enhancing the effect of THERATOPE STn-KLH cancer vaccine in patients with metastatic breast cancer by pretreatment with low-dose intravenous cyclophosphamide.

THERATOPE (Biomira Inc., Edmonton, AB, Canada) STn-KLH cancer vaccine induces strong antibody titers against both the synthetic STn epitope and against a natural mucin, OSM, which expresses STn-like epitopes. In prospective, randomized studies in patients with metastatic breast cancer treated at two cancer centers, the effect of different low-dose, immunomodulatory cyclophosphamide (cyclo) pretreatments on the response to THERATOPE STn-KLH was compared. Patients were randomized to receive either intravenous cyclo 300 mg/m2 on day -3, or oral cyclo 50 mg daily from days -14 to -3 inclusive, or no cyclo, before THERATOPE treatments. The anti-STn and anti-OSM antibody titers were higher in the patients who received cyclo intravenously before THERATOPE. Patients treated with cyclo intravenously and THERATOPE STn-KLH cancer vaccine lived significantly longer (projected median survival of 19.7 months versus actual median survival of 12.6 months, p = 0.0176) than those treated with the same STn vaccine with oral or no cyclo. Although it is not clear how the anti-STn antibody response modifies tumor biology, we noted that patients in the intravenously administered cyclo group had a lower percentage of patients showing progressive disease at 9 weeks, and that there was an inverse correlation between serum anti-STN antibody titer and growth of measurable tumors. There was no correlation between tumor growth and anti-KLH antibody titers. These data are consistent with a therapeutic effect of THERATOPE STn-KLH cancer vaccine and support development of a phase III study to explore this further.

Adenocarcinoma↗
PubMed2007

A clinical development paradigm for cancer vaccines and related biologics.

Therapeutic cancer vaccines are a heterogeneous group of complex biologics with distinctly different clinical characteristics than cytotoxic agents. The current clinical development paradigm used for oncology drug development is based on criteria developed for cytotoxic agents. More flexible and focused developmental guidelines are needed to address the unique characteristics of therapeutic cancer vaccines. Over the course of 1 year, the Cancer Vaccine Clinical Trial Working Group, representing academia and the pharmaceutical and biotechnology industries with participation from the US Food and Drug Administration, defined in a consensus process the cornerstones of a new clinical development paradigm for cancer vaccines and related biologics. Four major topics were addressed: (1) end points for clinical trials, (2) trial designs and statistical methods, (3) technical and developmental challenges, and (4) combination therapy. The proposed paradigm suggests therapeutic cancer vaccines to be investigated in 2 general types of clinical studies: proof-of-principle trials and efficacy trials. Proof-of-principle trials, which introduce a novel cancer vaccine into humans, should include a minimum of 20 or more patients in a homogenous, well-defined population in an adjuvant setting or without rapidly progressive disease in a metastatic setting to allow vaccines adequate time to induce biologic activity and should incorporate immune and molecular markers. Objectives should include initiation of a safety database, determination of dose and schedule, and demonstration of biologic activity as proof-of-principle. Biologic activity is defined as any effect of the vaccine on the target disease or host immune system using biologic markers as study end points, for example, clinical, molecular, or immune response. Immune response is demonstrated if determined in 2 separate, established and reproducible assays at 2 consecutive follow-up time points after the baseline assessment. If proof-of-principle trials show such immune response, or other biologic or clinical activity, efficacy trials may be initiated. If none of these end points is met, the clinical development plan should be reevaluated to decide if further development is warranted. Efficacy trials formally establish clinical benefit either directly or through a surrogate and are encouraged to be randomized studies. This is in contrast to single-arm phase 2 trials used for cytotoxic agents, which often use tumor response rate as the primary end point and historical controls as a comparator. Efficacy trials may use prospectively planned adaptive designs to expand from randomized phase 2 into phase 3 studies if well-defined trigger-point criteria are met, but the cost of incorporating such design elements should be carefully evaluated. Efficacy trials can also be exploratory randomized phase 2 trials or conventional phase 3 trials. In addition, conventional clinical end points can be adjusted to account for biologic features of cancer vaccines. The concept of efficacy trials allows for an early assessment of vaccine efficacy based on credible prospective data. This 2-phase developmental paradigm supports a more flexible, expeditious, and focused clinical developmental process with early and informed decision making. In addition, this report addresses clinical development challenges and issues for combination therapies.

Cancer Vaccines↗
PubMed2006

[New advances in clinical trials of cancer vaccines].

Currently, a range of cancer vaccine strategies are being tested including those using peptides, DNA/RNA, viral vectors, tumor cells, pulsed dendritic cells etc. Cancer vaccines can activate, recover or power the immune system to kill and eliminate tumor cells by expressing specific cancer antigens. New cancer vaccines must be first studied in animals and then tested for safety and effectiveness in three phases of clinical trials. Cancer vaccines have shown promise in clinical trials with many types of cancer. There are a lot of vaccines which can initiate a powerful immune response in some patients, and are generally well tolerated. Although there are dozens of cancer vaccines in advanced clinical trials, yet only a few phase III studies have been completed. Because they have failed to meet the goals of safety and effectiveness, this makes cancer vaccines still in an experimental stage. A number of promising new cancer vaccines have entered clinical trials, and we eagerly await their findings. In this article we reviewed new advances in clinical trials and the perspective in clinical use of cancer vaccines.

Cancer Vaccines↗
PubMed2002

On the power of chemical synthesis: immunological evaluation of models for multiantigenic carbohydrate-based cancer vaccines.

Synthetic carbohydrate cancer vaccines have been shown to stimulate antibody-based immune responses in both preclinical and clinical settings. The antibodies have been observed to react in vitro with the corresponding natural carbohydrate antigens expressed on the surface of tumor cells, and are able to mediate complement-dependent and/or antibody-dependent cell-mediated cytotoxicity. Furthermore, these vaccines have proven to be safe when administered to cancer patients. Until recently, only monovalent antigen constructs had been prepared and evaluated. Advances in total synthesis have now enabled the preparation of multivalent vaccine constructs, which contain several different tumor-associated carbohydrate antigens. Such constructs could, in principle, serve as superior mimics of cell surface antigens and, hence, as potent cancer vaccines. Here we report preclinical ELISA-based evaluation of a TF-Le(y)-Tn bearing construct (compound 3) with native mucin glycopeptide architecture and a Globo-H-Le(y)-Tn glycopeptide (compound 4) with a nonnative structure. Mice were immunized with one or the other of these constructs as free glycopeptides or as keyhole lymphet hemocyanin conjugates. Either QS-21 or the related GPI-0100 were coadministered as adjuvants. Both keyhole lymphet hemocyanin conjugates induced IgM and IgG antibodies against each carbohydrate antigen, however, the mucin-based TF-Le(y)-Tn construct was shown to be less antigenic than the unnatural Globo-H-Le(y)-Tn construct. The adjuvants, although related, proved significantly different, in that GPI-0100 consistently induced higher titers of antibodies than QS-21. The presence of multiple glycans in these constructs did not appear to suppress the response against any of the constituent antigens. Compound 4, the more antigenic of the two constructs, was also examined by fluorescence activated cell sorter analysis. Significantly, from these studies it was shown that antibodies stimulated in response to compound 4 reacted with tumor cells known to selectively express the individual antigens. The results demonstrate that single vaccine constructs bearing several different carbohydrate antigens have the potential to stimulate a multifaceted immune response.

Adjuvants, Immunologic↗
PubMed2006

Heat shock protein-based cancer vaccines.

The ability to duplicate the remarkable success of infectious disease vaccines in cancer, with durably robust and highly specific antitumor immune responses, has been long held as one of the keys in developing true "magic bullet" cancer therapies. This article attempts to explain why cancer vaccines have failed (so far), delineate the increasingly complex barriers that prevent the eliciting of effective antitumor immunity and examines the ability of heat shock protein-based vaccines to overcome these barriers. This article is not a definitive compendium of the huge body of relevant literature but rather focuses on the major concepts underlying active specific immunotherapy in general and heat shock protein vaccines in particular.

Antigen-Presenting Cells↗
PubMedDate not supplied

Cancer vaccines (1).

Several cancer vaccines are in various phases of clinical research. As vaccine therapy evolves, this method of treating and/or preventing cancer will become more common. Part 2 of this column will describe some of the current vaccine studies and where vaccine therapy may be headed in the future.

Antigens, Neoplasm↗
PubMed1996

Carcinoembryonic antigen as a target for cancer vaccines.

The vaccine approach to cancer therapy is still in the early stages. Since any immune response has a limited capacity, immunotherapeutic manipulations to destroy tumor will probably be most effective against small tumor masses or micrometastases. Consequently, immunotherapy with these CEA cancer vaccines may prove most effective in the adjuvant setting, where disease has been controlled or stabilized with conventional therapies. The development of CEA cancer vaccines involves many parameters, including the appropriate form of the vaccine, i.e., recombinant protein, peptides, vectors etc., the use of classical adjuvants and/or biological adjuvants such as cytokines, and the use of T cell costimulatory molecules. The integration of these parameters into the development of a cancer vaccine will be the challenge for the next decade [33].

Animals↗