All patients developed a flu-like syndrome but responded to non-prescription symptomatic treatment. No grade 4 adverse events were observed. No patients required antibiotic treatment suggesting that the side effects were most likely secondary to cytokine release rather than bacterial infection. Two patients died during the study. From the evaluable patients, 5 had progressive disease, 7 had stable disease, and 1 had a partial response. For the treated patients, median survival was reported to be days. Based on the efficacy and safety of the treatment, Lm-LLO-E7 is now being studied in a phase II trial in patients with advanced cervical cancer Other antigens are also being used in Listeria for vaccination, including PSA for prostate cancer and mesothelin for pancreatic cancer with intriguing preliminary results in early phase clinical trials.
The most common grade 3 or greater treatment-related adverse events were transient fever, lymphopenia, increase in hepatic transaminases and fatigue. Yeast derived vaccines are also currently being studied as potential cancer immunotherapy. Using yeast as a vector has several advantages, including easy engineering of tumor antigens and simple storage and transportation of the vector since heat-killed yeast are very stable. In a phase I study, yeast-CEA was evaluated for safety, tolerability, and clinical response in patients with metastatic CEA-expressing carcinoma who failed standard treatment.
Twenty-five patients were enrolled in the study, of which 20 had colon adenocarcinoma, 2 had rectal adenocarcinoma, one had pancreatic adenocarcinoma, one had NSCLC, and one had medullary thyroid cancer. Median baseline CEA was Patients received subcutaneous vaccines every 2 weeks for 3 months and then one dose monthly. The vaccine was well tolerated with the most common adverse effects being grade 1 or grade 2 injection-site reactions.
Only three grade 3 toxicities were reported which were injection-site reaction, vigorous immune response in one patient that resolved with high dose corticosteroids, and pain possibly confounded by progressing disease. The median survival after enrollment was 7 months. In 24 evaluable patients, 7 patients had declines in their serum CEA levels.
Five patients had stable disease beyond 3 months, and each of these 5 patients had a decrease in CEA levels. Given the success of T cell checkpoint inhibitors alone, and in combination, as well as the emergence of neoantigens following T cell checkpoint blockade, support the concept of combining tumor vaccines with T cell checkpoint inhibitors While perhaps logical, there have been relatively few studies completed to date.
Although the original clinical trial of ipilimumab used a gp peptide vaccine arm alone as a control, and also included a combination arm, no significant impact of the vaccine was demonstrated 2. This may be due to the limited strength of gp peptide vaccine and new trials with more contemporary antigens, such as neoantigens and better vectors regimens, should be considered. To date, most of the encouraging data with combination studies using T cell checkpoint inhibitors have come from studies with oncolytic viruses.
A single grade 5 event related to CNS disease progression was also seen. A larger patient randomized trial comparing the combination to ipilimumab alone has now been completed and results are pending. A large, randomized phase III clinical trial of T-VEC and pembrolizumab versus pembrolizumab alone is also under way in patients with advanced melanoma. Combination of the coxsackievirus CVAA21 and ipilimumab is currently being studied in a phase 1b trial in patients with advanced melanoma.
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The primary objective of this study will be to evaluate the safety and tolerability of multiple intratumoral injections of the combination, which will be assessed by incidence of dose-limiting toxicities in treatment. The secondary objective of the study is to investigate the objective response rate to the combination in patients with advanced melanoma A single-arm phase II trial of CVA21 and pembrolizumab is also underway in patients with advanced melanoma.
Other interesting combination trials would include vaccines and other T cell stimulants, such as cytokines. Using a similar HLA-A2-resricted gp peptide vaccine as used in the ipilimumab trial, Schwartzentruber and colleagues evaluated the vaccine in combination with high-dose interleukin-2 IL-2 in patients with advanced melanoma. The combination showed a significant improvement in objective response rate and PFS.
PFS was 2. The median OS was The adverse effects were similar in both groups with most toxicity attributed to expected ILrelated effects Other T cell agonists, such as interleukin IL , BB and OX40 agonists, would be expected to be of high interest with vaccines that can elicit antigen-specific T cell responses. While such combinations have shown therapeutic benefit in animal models, clinical trials have not been conducted to date.
Turning the corner on therapeutic cancer vaccines
An emerging and promising therapy for cancer is ACT. In ACT, genetically engineered or tumor-reactive T cells, which may be collected from peripheral blood or tumor-infiltrating lymphocytes, are used to treat patients. ACT therapy requires selection of an appropriate antigen for T cell targeting, optimizing the T cell phenotype for transfer, inclusion of non-myeloablative conditioning regimens, and post-transfer T cell support with IL-2 or related immune stimulating factors.
The use of chimeric antigen receptors CARs utilize single chain antibody Fab fragments with associated TCR signaling elements have shown significant promise in hematologic malignancies. The use of CAR-modified T cells targeting the B cell-specific antigen CD19 have shown remarkable success in treatment of acute lymphoblastic leukemia.
Cancer vaccines | American Cancer Society
A recent abstract by Grupp et al. At the median follow up of 8 months, 16 patients still had ongoing complete response showing the possibility of a long-term response rate The most common toxicity associated with CAR-modified T cell therapy is cytokine release syndrome CRS , which is an inflammatory process that can lead to a range of clinical presentations from flu-like constitutional symptoms to multisystem organ failure Neurologic toxicity has also been reported. The use of vaccines encoding similar antigens to stimulate adoptively transferred or CAR T cells have been suggested by combination studies in animal models.
Further, T cell persistence has been a hallmark of therapeutic response in small clinical trials, and thus the use of vaccines to boost T cell responses and maintain an expanded population of tumor-antigen specific T cells is a logical strategy. To date, these studies have not yet been done. Strategies to combine radiation therapy and immunotherapy are also currently being developed based on observations of an abscopal effect when radiation was used in combination with T cell checkpoint inhibitors Although the mechanisms are not completely understood, it is possible that radiation increases release of tumor-associated antigens, which results in enhanced antigen presentation and induction of T cell immune responses Furthermore, radiation may enhance the expression of MCH class I molecules that may allow for increased exposure of antigens to cytotoxic T cells through peptide-MHC complexes.
Also in response to radiation, there is an increased degradation of proteins and generation of new peptides that enables new peptides to be presented on MHC class 1 molecule In addition to these mechanisms, radiation can damage cancer cells leading to the release of immunostimulatory molecules, such as the high mobility group box 1 HMGB1 protein. HMGB1 molecules interact with toll-like receptor 4 TLR4 antigen presenting dendritic cells leading to a more enhanced presentation of dying tumor cell antigens 30 , The effects of radiation may be synergistic when used in combination with immunotherapy.
For example, PD-1 blockade in combination with localized radiation therapy resulted in significantly longer median survival in mice with intracranial gliomas compared to animals treated with either monotherapy In breast cancer mouse models, radiation and CTLA-4 blockade was found to have a greater abscopal effect against secondary sites than either treatment alone Combination of radiation and immunotherapy is being explored in clinical trials as well. Gulley et al. Seventeen of 19 patients in the combination group completed their full course of treatment. Chi et al.
Patients were injected with autologous immature dendritic cells into the tumor along with radiotherapy. Twelve of 14 patients finished the vaccinations. The treatment was well tolerated with no evidence of autoimmune disease. Ten patients showed complete responses 2 weeks after receiving the vaccine.
T-Cell Responses to Tumor Peptides
Six patients showed increased NK cell cytotoxic activity Similar to radiation, chemotherapy can also help induce an immune response against cancer by promoting antigen release among other mechanisms. Cyclophosphamide has been known for years to potentially help promote anti-tumor immunity by targeting regulatory T cells. For example, Lutsiak et al. Furthermore, cyclophosphamide may have the ability to enhance higher avidity T cell responses against specific tumors, although inclusion of cyclophosphamide in vaccine regimens has not been associated with prolonged survival in vaccine studies Lutz et al.
These immunotherapies have not been able to induce any significant immune activity. It is important to note, however, that the cyclophosphamide could not be directly linked to the formation of the tertiary aggregates in this trial. The role of cyclophosphamide remains controversial and there is the theoretical risk that it may be deleterious due to the non-specific mechanism of action and potential for depletion of effector T cells in addition to regulatory T cells.
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In a dose-ranging study, Emens et al. Based on preclinical and clinical studies, the combination of chemotherapy and vaccine therapy may play a substantial role in future cancer treatments. This general concept has also been demonstrated in the setting of T cell checkpoint blockade resistance, in which tumor cells expressing oncogenic Kras and lacking p53 were not sensitive to checkpoint inhibition These studies support a possible role for chemotherapy in enhancing host anti-tumor immunity, but further clinical studies will be required to confirm the efficacy of the approach and better define the optimal agents and schedule of administration.
Other chemotherapy agents, as well as targeted therapies, may also mediate tumor cell antigen release and enhance T cell priming. These findings suggest that cytotoxic drugs might be able to enhance T cell infiltration into established tumors and support the hypothetical strategy of combining cytotoxic agents with vaccines that can help prime and expand such T cell responses.
Further studies of individual cytotoxic drugs with vaccines may be a fruitful avenue for future research. Since infectious disease vaccination is more effective in prophylaxis against disease, one approach to consider is to use cancer vaccines in the preventive setting prior to tumor-induced immune suppression. Historically, most tumor vaccines have been used to try to suppress already established and growing tumors.
Few clinical trials have been done with tumor vaccines prior to cancer progression. Early prophylactic treatment may show better outcomes since it can potentially prepare the immune system to detect tumor cells before tumors cells have the chance to activate immune suppression mechanisms. Vaccines against viruses such as the hepatitis B virus HBV and human papillomavirus HPV have shown significant success in liver cancer and cervical cancer prevention, respectively 42 , In spite of the success of viral antigen based vaccines, the use of non-viral antigens against cancers has not made similar successful leaps to the prevention setting despite preliminary evidence of T cell priming and an acceptable safety profile.
This may relate to concerns over regulatory pathways to approval, the large samples sizes and follow-up times needed to conduct such studies or the economic costs associated with prevention studies in oncology. Nevertheless, several murine cancer models have demonstrated significant benefit in tumor prevention with specific vaccine approaches, whereas vaccination with the same vaccine against metastatic cancer had negligible therapeutic impact 44 , Kimura et al.
The authors hypothesized that the T cell responders may have already had some degree of immune memory against MUC-1 at baseline and vaccination served as a booster expanding the MUC-1 T cell population The authors also reported that there were few adverse events but some patients did have evidence of high myeloid-derived suppressor cells suggesting that even in patients with advanced adenomas, the immune system may already be compromised.
An emphasis on defining appropriate high-risk populations and methods for limiting samples sizes and financially supporting prevention trials may be an appropriate path forward for tumor vaccines. Great progress has been made in the clinical implementation of tumor immunotherapy for the treatment of cancer. Antigens likely play an important role in most forms of immunotherapy, and recent discovery of a correlation between neoantigen emergence and therapeutic response with T cell checkpoint inhibitors has provided renewed interest in the development of vaccines for cancer therapy.
Although the optimal antigen, dose, delivery vector, route, schedule, and adjuvant approaches are not established, the ability to rapidly screen the cancer genome in individual patients and development of personalized vaccines based on the results are being actively investigated for feasibility and effectiveness.