Traditional cancer drugs are cytotoxic agents, meaning that they kill cells. Although most chemotherapeutics preferentially affect rapidly dividing cells (i.e., cancer cells) they can not differentiate between malignant and normal cells. The unavoidable toxicity to normal cells often results in treatment-related toxicities such as increased susceptibility to bleeding and infection, mucositis, nausea and vomiting, hair loss, etc. This nonspecific approach to cancer treatment makes it more suitable for use in disease settings in which the tumor burden is high, such as advanced or metastatic disease. Therapeutic cancer vaccines belong to a newer class of targeted cancer therapies. Like innovative treatments such as Gleevec & Herceptin. Most cancer vaccines in development are designed to attack only malignant cells. By targeting tumor cells with high specificity, this new class of treatments tends to be associated with less toxicity compared with traditional cancer drugs. Despite the varied approaches employed by the many therapeutic cancer vaccines in development, they all share one fundamental goal: to program a patient’s immune system to attack the patient’s cancer. Some vaccines utilize antigens (any substance capable of stimulating an immune response) that are known to be associated with certain types of tumors. In recent years, there was an increased interest on so-called unique antigens that are products of random mutations arising in the course of tumor cells’ uncontrolled cell divisions. These led researchers’ interest and work on personalized cancer vaccines that use the patients’ own tumor cells to generate immune response specific to the patients’ own cancers.
Approaches for development of personalized cancer vaccine:
One of the approaches to develop personalized cancer vaccines is the dendritic cell– based therapy. Patient’s dendritic cells (DC) are stimulated ex vivo through exposure to tumor-cell lysate, fusion with tumor cells, infected by virus containing a gene or exposure to purified peptides. A single or a few peptides from cancer-specific antigens can be used to pulse the patient’s own DC. Given back to the patient, DC will present the tumor antigens to the T cells in the effector arm of the immune system.
Another approach involves use of irradiated tumor cells. Patients’ tumor cells are irradiated to remove the harmful factor from the cell and then it is mixed with BCG.
Tumor derived Heat shock protein peptide complex are also being used for development of such vaccines. Heat shock proteins are a group of proteins found in all cells in all life forms. They function as chaperones, helping proteins fold while also transporting them throughout the cell. In their chaperone function, they bind with a large repertoire of proteins and peptides. Recent studies demonstrate an essential role of HSPs (complexed with antigenic peptides) in the priming of immune response by cells undergoing necrotic death. Recent studies have shown greater efficiency of such vaccines against fibrosarcoma, leukaemia, melanoma, and lung, colon, breast, and prostate cancers.
Commercial products under clinical trials:
OncoVAX is vaccine prepared individually from each patient’s tumor cells. After surgical resection of the tumor, cells from the tumor are irradiated and then mixed with the adjuvant bacille Calmette–Gue´rin (BCG, an attenuated strain of bacteria that can boost immune response to a vaccine). It is designed to stimulate a specific immune response against each patient’s own cancer.
OncoVAX was evaluated in the adjuvant setting (in conjunction with another treatment—in this case, surgery) in a phase 3 clinical trial involving patients with stage II and III colon cancer. In the study, patients were randomized to receive either OncoVAX or observation after surgical resection of the primary tumor. The study found that with a 5.8-year median follow-up, there was a statistically significant benefit associated with vaccine for both recurrence-free survival and overall survival (OS) in stage II (earlier-stage) patients (n = 157) but not in stage III (advanced-stage) patients (n = 84). In the trial, OncoVAX was associated with a significant improvement in five-year recurrence-free survival (79% vs. 62% for vaccine and control groups, respectively; P = 0.009). OS was also significantly improved in stage II patients receiving vaccine (82.5%) compared with comparable patients in the control arm (72.7%; P = 0.010). A phase 3 confirmatory trial in stage II colon cancer is planned.
Oncophage :
Oncophage is an autologous vaccine that consists of complexes of heat shock proteins and their associated peptides derived from patients’ own tumor cells. These complexes (HSPPCs) comprise a sort of antigenic “fingerprint” that is unique to each patient’s cancer. The vaccine is designed to stimulate a specific immune response against cancer cells bearing this fingerprint. Oncophage was evaluated in a phase 3 study, which randomized 728 patients with nonmetastatic renal cell carcinoma (RCC; kidney cancer) at high risk for recurrence to receive either nephrectomy alone (observation arm) or nephrectomy plus Oncophage vaccination. Subgroup analyses demonstrated that in 361 patients (60% of randomized eligible patients) with earlier-stage disease and it increased risk of recurrence [stage I (high histological grade), stage II (high-grade), or stage III T1, T2, and T3a (low-grade)] treatment with Oncophage resulted in prolonged time to recurrence.
Provenge :
Provenge consists of patient-derived DC that have been cultured with a “delivery cassette” that contains a version of the prostate cancer–associated antigen prostatic acid phosphatase (PAP) (found in about 95% of prostate cancers) and the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). It is designed to activate specialized immune cells called T cells to recognize and destroy cells bearing the PAP antigen. In contrast to personalized vaccines using patient’s own tumor to derive a large repertoire of antigens, Provenge uses a generic antigen common in prostate carcinoma. A phase 3 trial of Provenge involving 127 patients with asymptomatic, androgen-independent, metastatic prostate cancer missed the primary end point of time to progression. However, the final three-year follow-up data showed a median survival benefit of 21%, or 4.5 months, and a threefold improvement in survival at 36 months compared with placebo; regardless of Gleason score. A second phase 3 trial, involving 98 men with asymptomatic, metastatic, androgen-independent prostate cancer, corroborated findings from the first trial: Patients who received vaccine had a 19.0-month median survival time compared with 15.7 months for patients who received placebo, representing a 21% improvement. Integrated analysis of data from both trials showed a statistically significant survival benefit among the overall ITT population of 225 patients: Patients who received Provenge had a median survival of 23.2 months compared with 18.9 months for patients who received placebo. A third, pivotal phase 3 trial is ongoing to evaluate Provenge as a treatment for advanced prostate cancer.
MyVax:
MyVax personalized immunotherapy is an autologous active cancer immunotherapy consisting of recombinant patient-specific idiotype that is conjugated to KLH, an immunogenic carrier protein, and administered along with GM-CSF adjuvant. Results from a phase 2 study showed that 9 of the 21 patients in the study remained progression-free in their last clinical follow-up at 56 to 78 months following chemotherapy. A pivotal phase 3 study to measure PFS in patients with follicular non-Hodgkin’s lymphoma is underway.
Stimuvax:
Stimuvax, a non-patient-specific vaccine, consists of a synthetic peptide derived from the tumor-associated antigen MUC-1 encapsulated in a liposome (a phospholipid shell intended to facilitate and improve treatment delivery). It is designed to neutralize the immunosuppressive effect of MUC-1 to better enable the immune system to target the cancer. A phase 2, randomized, open-label trial evaluated Stimuvax in patients with stage IIIB or IV non-small cell lung cancer (NSCLC) whose disease was stable or had responded to treatment following completion of first-line standard chemotherapy, with or without radiation treatment. Final analysis of the trial, which involved 171 patients, showed a survival advantage associated with vaccination for patients with stage IIIB disease (earlier-stage disease and therefore associated with better prognosis; n =65) but not for patients with stage IV disease (advanced-stage disease, worse prognosis; n= 106). In the study, median survival was 30.6 months for stage IIIB patients who received vaccine compared with 13.3 months for stage IIIB patients in the control arm. A 1300-patient phase 3 trial has recently launched in patients with stage IIIA or IIIB loco regional NSCLC.
Conclusion:
One of the clear advantages to personalized cancer vaccines is the excellent safety profile and higher efficacy, which makes their use in the adjuvant or earlier-stage disease setting more suitable than more conventional treatments such as conventional chemotherapy or radiotherapy. The data generated till date indicates that vaccine therapy is safe, and no significant autoimmune reactions are observed even on long-term follow-up. Such a safety profile would indicate the potential for a high quality of life index, which is a unique feature when compared with serious and some times life threatening the adverse effects associated with traditional cancer treatments. Despite a general consensus that personalized cancer vaccines appear to be safe and well tolerated, it is more difficult to draw conclusions regarding their efficacy in larger populations. To date, there have only been approximately 15 randomized phase 3 trials conducted with personalized cancer vaccines. However, there are several examples that indicate treatment activity is present in subsets of cancer patients and there is a likelihood of more number of such products entering in clinical phases in near future.
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