for ex vivo cytotoxic T lymphocyte induction 9 , 10 and later formulated the autologous formalin-fixed tumor vaccine (AFTV) for in vivo induction of killer lymphocytes. 13 , 14 A Phase II randomized clinical trial showed that AFTV prevents recurrence of hepatocellular carcinoma after surgery, 8 and another pilot study revealed its therapeutic effectiveness associated with absence of severe treatment-related complications in cases of recurrent and residual GBM. 6 Therefore, the present prospective clinical trial was initiated for evaluation of the therapeutic
Yoshihiro Muragaki, Takashi Maruyama, Hiroshi Iseki, Masahiko Tanaka, Chie Shinohara, Kintomo Takakura, Koji Tsuboi, Tetsuya Yamamoto, Akira Matsumura, Masao Matsutani, Katsuyuki Karasawa, Katsunori Shimada, Naohito Yamaguchi, Yoichi Nakazato, Keiki Sato, Youji Uemae, Tadao Ohno, Yoshikazu Okada and Tomokatsu Hori
Eiichi Ishikawa, Yoshihiro Muragaki, Tetsuya Yamamoto, Takashi Maruyama, Koji Tsuboi, Soko Ikuta, Koichi Hashimoto, Youji Uemae, Takeshi Ishihara, Masahide Matsuda, Masao Matsutani, Katsuyuki Karasawa, Yoichi Nakazato, Tatsuya Abe, Tadao Ohno and Akira Matsumura
G lioblastoma multiforme (GBM) is the most common primary brain tumor, and it has a dismal prognosis despite aggressive treatment using surgery, radiation therapy, and an alkylating agent, temozolomide (TMZ). 3 , 23 Recently, a growing interest in therapeutic modalities based on tumor-specific immune reactions for treatment of patients with GBM has emerged. 6 , 21 We have developed an autologous formalin-fixed tumor vaccine (AFTV) for in vivo induction of killer lymphocytes, 5 , 16 suppression of recurrence of hepatocellular carcinoma after primary
T o T he E ditor : We recently evaluated our experience with the use of autologous formalin-fixed tumor vaccine in patients with intracranial gliomas. During this process, we discovered an error in the calculated median overall survival time that we had noted in our original publication, “Phase I/IIa trial of autologous formalin-fixed tumor vaccine concomitant with fractionated radiotherapy for newly diagnosed glioblastoma. Clinical article” ( J Neurosurg 115: 248–255, 2011). As demonstrated in Fig. 3 right (p. 252) of that article, the overall survival
Andrew E. Sloan, Roger Dansey, Lucia Zamorano, Geoffrey Barger, Caroline Hamm, Fernando Diaz, Roy Baynes and Gary Wood
This trial was designed to determine the ability of autologous whole–tumor cell vaccines to induce cell-mediated immune responses in patients with recurrent malignant glioma, as well as to determine whether combining such vaccination with adoptive transfer of in vitro activated T lymphocytes prolongs patient survival.
Nineteen patients with recurrent malignant glioma, in whom previous external beam radiotherapy and at least one course of chemotherapy had failed were vaccinated twice with irradiated autologous whole tumor cells by using granulocyte-marcrophage colony–stimulating factor as an adjuvant. Patients then underwent leukapheresis followed by adoptive transfer of peripheral blood lymphocytes activated in vitro with anti-CD3 and interleukin-2. In vivo immune response, radiological response, clinical outcome, and survival were monitored.
Seventeen patients developed a delayed-type hypersensitivity (DTH) response to vaccination that appeared to be directed against the autologous tumor. In eight patients there was radiological evidence of a response and in five there was evidence of clinical improvement. Median survival was 12 months (range 6–28 months), and both the presence of a DTH response and the radiological response correlated with survival (p < 0.02 and p < 0.04, respectively).
These preliminary results suggest that autologous whole–tumor cell vaccines induce a cell-mediated immune response, which appears to be tumor specific in most patients. Furthermore, vaccination combined with adoptive immunotherapy with in vitro activated cells may induce a radiologically demonstrated tumor response and improved survival despite a condition of advanced disease and immunosuppression resulting from previous treatment or tumor burden. Further studies of immunotherapy are warranted.
John H. Chi, Amith Panner, Kristine Cachola, Courtney A. Crane, Joseph Murray, Russell O. Pieper, C. David James and Andrew T. Parsa
treated and untreated groups. Discussion The anecdotal success of some recent clinical trials in which tumor vaccines were used have sparked renewed interest in harnessing the immune system to fight cancer. 9–11 Despite promising results in animal models, trials of cancer immunotherapy in humans have been less successful. Although antigens for certain cancers have been recognized, the majority of cancers in clinical practice have no known TAA. Understanding the factors that influence expression and regulation of TAAs may aid in discovering new antigens and
Norimoto Nakahara, Hideho Okada, Timothy F. Witham, Jason Attanucci, Wendy K. Fellows, William H. Chambers, Ajay Niranjan, Douglas Kondziolka and Ian F. Pollack
+ (cytotoxic) T cells play a central role in antitumoral immunity activated by cytokine gene—transduced tumor cell vaccination. 7, 11 Notwithstanding this immunological response, it is noteworthy that administration of one of the vaccines alone was not able to achieve long-term survival in this aggressive tumor model system. Although the mechanism by which radiosurgery potentiates the effects of the tumor vaccine on animal survival remains conjectural, several factors may be involved. First radiosurgery may simply delay tumor growth sufficiently to allow time for the
Praveen Deshmukh, Roberta P. Glick, Terry Lichtor, Risha Moser and Edward P. Cohen
fibroblasts for cytokine administration is an attractive method of therapy because many of the side effects of high-dose systemic administration have not been observed. The intracerebral injection of cytokine-secreting cells alone has led to no significant long-term side effects. 11, 18 Allogeneic rather than syngeneic cells were chosen for local cytokine administration for several reasons. It has been shown that foreign MHC determinants can augment the immunogenic properties of a tumor vaccine. 7, 9, 12, 14, 16, 17, 24 Genetic modification of a cell line rather than of
Linda M. Liau, Keith L. Black, Robert M. Prins, Steven N. Sykes, Pier-Luigi DiPatre, Timothy F. Cloughesy, Donald P. Becker and Jeff M. Bronstein
effective CNS antitumor immunoreactivity can be generated with dendritic cell—based tumor vaccines. Further comparisons between the immunogenic efficacy of dendritic cells pulsed with undefined multiple epitopes (that is, from acid-eluted glioma surface peptides or tumor RNA) and a defined single tumor—specific epitope will need to be evaluated if and when a glioma-specific antigen is identified. Meanwhile, our present method for acid extraction of MHC Class I—bound peptides from glioma cells appears to be a feasible and effective technique for antigen isolation in brain
Jorgen Kjaergaard, Li-Xin Wang, Hideyuki Kuriyama, Suyu Shu and Gregory E. Plautz
found to be relatively ineffective tumor vaccines, prompting exploration of more potent cellular glioma vaccines. Dendritic cells are the most potent antigen-presenting cells and the only cells capable of activating naive T lymphocytes. 4 They normally function by acquiring antigens in peripheral tissues before migrating to secondary lymph tissues to process and present antigens to CD4 + and CD8 + T cells. Note that DCs loaded with various preparations derived from malignant cells have demonstrated substantial therapeutic efficacy in preclinical models of glioma
Gregory E. Plautz, Gene H. Barnett, David W. Miller, Bruce H. Cohen, Richard A. Prayson, John C. Krauss, Mark Luciano, Debra B. Kangisser and Suyu Shu
immunotherapy for the treatment of malignant gliomas. The study design is based on overwhelming preclinical data documenting that LNs draining a progressive tumor or tumor vaccine are a rich source of tumor-sensitized T cells. A key feature of this clinical protocol is the use of autologous tumor cells to stimulate T lymphocytes in the draining LN. The antigens from malignant gliomas that are recognized by T lymphocytes have not yet been characterized, and it is not known if they are unique to each tumor or are shared. However, we reasoned that short-term cultured autologous