Autologous Cell Vaccine Research Articles

Treatment of brain tumors with autologous cancer cell vaccines and radiotherapy

Treatment of brain tumors with autologous cancer cell vaccines and radiotherapy

Tumor vaccines--application to childhood cancer.

Currently, several clinical studies explore the therapeutic potential of tumor vaccines which are genetically modified to produce immunostimulatory molecules as a complementary approach for conventional cancer therapy. In this review the immunological basis and the preclinical design of such vaccine strategies are described with particular emphasis to acute leukemia and neuroblastoma. The role of cytokines, chemokines and costimulatory surface molecules for generation of tumor vaccines is summarized, and the advantages and disadvantages of autologous, allogenic and dendritic cell vaccines are discussed. Finally, combination-immunogens are introduced as a potent means of enhancing the anti-tumor response.

The feasibility of preparing autologous melanoma cell vaccine from small tumors for post-operative adjuvant treatment

The feasibility of preparing autologous melanoma cell vaccine from small tumors for post-operative adjuvant treatment

A Phase I Randomized Study of Subcutaneous Adjuvant IL-2 in Combination with an Autologous Tumor Vaccine in Patients with Advanced Renal Cell Carcinoma

We performed a prospective, randomized study to determine whether subcutaneous administration of interleukin-2 (IL-2) in combination with an autologous renal cell vaccine is feasible and can potentiate antitumor immunity. Seventeen patients with metastatic renal cell carcinoma underwent surgical resection with preparation of an autologous tumor cell vaccine. Patients were vaccinated intradermally twice at weakly intervals with 10(7) irradiated tumor cells plus bacillus Calmette-Guérin, and once with 10(7) tumor cells alone. Patients were randomized to one of three groups: no adjuvant IL-2, low-dose IL-2 (1.2 x 10(6) IU/m2), or high-dose IL-2 (1.2 x 10(7) IU/m2). IL-2 was administered subcutaneously on the day of vaccination and the subsequent 4 days. Immune response was monitored by delayed-type hypersensitivity (DTH) response to tumor cells as compared with normal autologous renal cells. Sixteen of 17 patients received vaccine therapy. Four patients developed cellular immunity specific for autologous tumor cells as measured by DTH responses; two had received no IL-2 and two had received high-dose IL-2. There were two partial responses (PR) noted, both in patients who received high-dose IL-2. One responding patient was DTH(+) and one was negative. A third patient who was DTH(+) after vaccination with no IL-2 had a dramatic PR after receiving IL-2 subcutaneously in a subsequent protocol. Prospective testing of response to recall antigens indicated that only 5 of 12 tested patients were positive, including both clinical responders. These data suggest that subcutaneously administered adjuvant IL-2 does not dramatically augment the immunologic response to autologous renal cell vaccines as determined by the development of tumor-specific DTH response.

The effect of combined expression of interleukin 2 and interleukin 4 on the tumorigenicity and treatment of B16F10 melanoma

The recent use of interleukin 2 (IL-2) and interleukin 4 (IL-4) single cytokine modified tumour cells in rodent models has demonstrated a potential use of these cytokines to produce autologous cancer cell vaccines. Here we compare the potential therapeutic benefit of transduction with IL-2 or IL-4 alone, and combined IL-2 + IL-4 in B16F10 cells, a murine malignant melanoma of poor immunogenicity. Transduction of B16F10 cells (MHC class I and II negative) to express either IL-2 or IL-4 alone delays the formation of tumours, IL-4 being more effective than IL-2. However, combined expression of IL-2 + IL-4 reduces tumorigenicity more than either cytokine alone. The eventual formation of tumours may result from loss of gene expression, and preliminary results suggest methylation of the retroviral long terminal repeat (LTR), rather than loss of the transduced DNA sequences. Histological examination of tumours expressing either IL-2 or IL-4 alone shows a non-specific inflammatory reaction with an increased tissue infiltrate of immune effectors (monocytes/macrophages, lymphocytes, granulocytes) localised around the tumour. In comparison, when cells expressing combined IL-2 + IL-4 were injected there were more granulocytes present, and perhaps more importantly, these were mainly localised within the tumour. The benefit of combined IL-2 + IL-4 expression results from a local rather than systemic effect as the growth of tumours from cells expressing IL-2 or IL-4 alone injected at distant sites was comparable with a single inoculation of cells expressing either cytokine alone. However, when cells expressing single cytokines IL-2 or IL-4 were mixed and injected at the same site, in comparison with the clonal population of cells expressing combined IL-2 + IL-4, tumour growth was characteristic of IL-4 alone rather than IL-2 + IL-4. Treatment of established tumours with a single injection of lethally irradiated tumour cells expressing IL-2 + IL-4 was sufficient to either reject tumours, or at least delay further tumour development. Furthermore, treatment stimulated an initial non-specific immune reaction that lead to a systemic immunity. Lethally irradiated wild-type cells were also successful in treating some established tumours, although this did not induce any systemic immunity. However, although successful in treatment studies, neither wild-type nor combined IL-2 + IL-4 expressing cells were able to vaccinate animals against a subsequent challenge with live wild-type tumour. These results indicate a potential therapeutic benefit with the use of combination IL-2 + IL-4 transduction of autologous cancer cells.

221 Active specific immunotherapy (ASI) in patients with metastatic melanoma (MM)

Background ASI has some promise in the treatment of patients (pts) with MM. Several clinical studies have demonstrated both humoral and cellular responses against melanoma antigens in vitro and an influx of tumor infiltrating lymphocytes in regressing metastatic lesions in MM pts. In general, vaccination with whole cell vaccines, either autologous or allogenic results in generation of melanoma specific delayed type hypersensitivity (DTH) reactivity in vivo. Objectives The purpose of our study was to reach maximal DTH response in individual MM pts and to evaluate whether the magnitude of these responses correlated with (progression-free) survival. Methods 44 MM pts were treated with autologous cell vaccines (216x, the first 2 admixed with BCG). Twenty-two pts had no evidence of disease after metastatectomy (NED group), neither clinically nor pathologically. The other 22 pts (ED group) had either incomplete resection of MM (n = 9) or still clinical evidence of MM (n = 13). Vaccines were prepared from material obtained after surgery according to a standardized procedure. Results The majority of pts in the ED-group (median survival 7 months) did not show an important DTH response. Peripheral blood lymphocytes (PBLs) showed strongly decreased responses to mitogens and PPD, which did not change after vaccination. In contrast, the majority of pts in the NED group (median survival 16+ months) showed a high DTH response and DTH reactivity correlated with survival. PBL responsiveness to PPD was strongly enhanced after vaccination. Conclusion In particular, in NED MM pts improvement of vaccine preparation by maneuvers, which enhance DTH response should be further explored.

Immunotherapy with irradiated autologous leukemic cells in patients with B-CLL in early stages

In this study 10(7) peripheral blood mononuclear cells including on average 78.56% CD19+/CD5+ lymphocytes were irradiated, and then administered intradermally as an anti-cancer vaccine to seventeen patients with B-cell chronic lymphocytic leukemia (B-CLL) at early stages (twelve injections, four at a weekly interval followed by eight vaccines given every two weeks). In eight out of seventeen patients, in the first two injections, irradiated leukemic cells were mixed with bacillus Calmette-Guerin (BCG) to improve the efficacy of therapy by additional induction of innate immunity. A hematological improvement (as defined by a >25% reduction of leukocyte count) to autologous leukemic cell vaccines was observed in 5/17 patients, stabilisation of disease in 5/17 patients and in 7/17 patients there was no response to immunotherapy. In seven patients significant increase of the lymphocyte doubling time was noted (p=0.02). There was no impact of BCG for immune responses or clinical outcome of vaccinated patients, but there was a significant increase of the absolute counts of CD3+ as well as of CD3+/CD4+ and CD3+/CD8+ T cells during the vaccination period. We observed a significant improvement of the phagocytic function of autologous dendritic cells generated from peripheral blood monocytes obtained from patients with B-CLL after the end of immunotherapy (p=0.006). An association between the clinical outcome and the percentage of leukemic cells positive for expression of ZAP-70 and CD38 was noted. In conclusion, our results demonstrated the feasibility and safety of autologous irradiated leukemic cell immunotherapy in patients with B-CLL. As we noted immunological, and to some extent, clinical responses, this approach merits further investigation, including the use of adjuvants other than BCG.