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Therapeutic response in patients with advanced malignancies treated with combined dendritic cell-activated T cell based immunotherapy and intensity-modulated radiotherapy.

Hasumi K, Aoki Y, Watanabe R, Hankey KG, Mann DL - Cancers (Basel) (2011)

Bottom Line: Successful cancer immunotherapy is confounded by the magnitude of the tumor burden and the presence of immunoregulatory elements that suppress an immune response.We hypothesized that radiation would lower the tumor burdens, decrease the number/function of regulatory cells in the tumor environment, and release products of tumor cells that could be acquired by intratumoral injected immature dendritic cells (iDC).These results demonstrate the safety and effectiveness of this multimodality strategy combining immunotherapy and IMRT in patients with advanced malignancies.

View Article: PubMed Central - PubMed

Affiliation: Hasumi International Research Foundation, Tokyo Research Center, 1-44-6 Asagaya-kita, Suginami- ku, Tokyo 166-0001, Japan. dmann001@umaryland.edu.

ABSTRACT
Successful cancer immunotherapy is confounded by the magnitude of the tumor burden and the presence of immunoregulatory elements that suppress an immune response. To approach these issues, 26 patients with advanced treatment refractory cancer were enrolled in a safety/feasibility study wherein a conventional treatment modality, intensity modulated radiotherapy (IMRT), was combined with dendritic cell-based immunotherapy. We hypothesized that radiation would lower the tumor burdens, decrease the number/function of regulatory cells in the tumor environment, and release products of tumor cells that could be acquired by intratumoral injected immature dendritic cells (iDC). Metastatic lesions identified by CT (computed tomography) were injected with autologous iDC combined with a cytokine-based adjuvant and KLH (keyhole limpet hemocyanin), followed 24 h later by IV-infused T-cells expanded with anti-CD3 and IL-2 (AT). After three to five days, each of the injected lesions was treated with fractionated doses of IMRT followed by another injection of intratumoral iDC and IV-infused AT. No toxicity was observed with cell infusion while radiation-related toxicity was observed in seven patients. Five patients had progressive disease, eight demonstrated complete resolution at treated sites but developed recurrent disease at other sites, and 13 showed complete response at various follow-up times with an overall estimated Kaplan-Meier disease-free survival of 345 days. Most patients developed KLH antibodies supporting our hypothesis that the co-injected iDC are functional with the capacity to acquire antigens from their environment and generate an adaptive immune response. These results demonstrate the safety and effectiveness of this multimodality strategy combining immunotherapy and IMRT in patients with advanced malignancies.

No MeSH data available.


Related in: MedlinePlus

Sequential events in the treatment protocol.
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f1-cancers-03-02223: Sequential events in the treatment protocol.

Mentions: Figure 1 illustrates an overview of the treatment protocol. Prior to treatment, the extent of disease and the location of metastases were established by PET-CT (Positron Emission Tomography—Computed Tomography). The patients underwent leukapheresis to obtain monocytes for differentiation into iDC and a monocyte depleted T-cell enriched population for preparation of activated T-cells (AT). After preparation of these reagents, a portion of the iDC was combined with lymphocyte conditioned media, a multi-cytokine based adjuvant (LCM), and KLH. This cell mixture was equally divided based on the number of sites to be injected, the volume of each aliquot was adjusted to ∼2 mL with PBS, and the individual lesions were injected under CT guidance. AT were infused the following day. Approximately 3 days later, the injected tumor sites received Intensity-Modulated Radiotherapy (IMRT) in divided doses. Two to three days following the last dose of radiation, the tumor sites were again injected with iDC suspended in LCM (without KLH) and AT infused the next day. Blood samples were obtained prior to protocol initiation and periodically thereafter to monitor serum levels of tumor markers and the development of anti-KLH antibodies. The PET-CT exams were repeated 6 weeks after the last treatment and periodically thereafter. The treatment cycle was repeated for several patients who developed lesions at new sites.


Therapeutic response in patients with advanced malignancies treated with combined dendritic cell-activated T cell based immunotherapy and intensity-modulated radiotherapy.

Hasumi K, Aoki Y, Watanabe R, Hankey KG, Mann DL - Cancers (Basel) (2011)

Sequential events in the treatment protocol.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757414&req=5

f1-cancers-03-02223: Sequential events in the treatment protocol.
Mentions: Figure 1 illustrates an overview of the treatment protocol. Prior to treatment, the extent of disease and the location of metastases were established by PET-CT (Positron Emission Tomography—Computed Tomography). The patients underwent leukapheresis to obtain monocytes for differentiation into iDC and a monocyte depleted T-cell enriched population for preparation of activated T-cells (AT). After preparation of these reagents, a portion of the iDC was combined with lymphocyte conditioned media, a multi-cytokine based adjuvant (LCM), and KLH. This cell mixture was equally divided based on the number of sites to be injected, the volume of each aliquot was adjusted to ∼2 mL with PBS, and the individual lesions were injected under CT guidance. AT were infused the following day. Approximately 3 days later, the injected tumor sites received Intensity-Modulated Radiotherapy (IMRT) in divided doses. Two to three days following the last dose of radiation, the tumor sites were again injected with iDC suspended in LCM (without KLH) and AT infused the next day. Blood samples were obtained prior to protocol initiation and periodically thereafter to monitor serum levels of tumor markers and the development of anti-KLH antibodies. The PET-CT exams were repeated 6 weeks after the last treatment and periodically thereafter. The treatment cycle was repeated for several patients who developed lesions at new sites.

Bottom Line: Successful cancer immunotherapy is confounded by the magnitude of the tumor burden and the presence of immunoregulatory elements that suppress an immune response.We hypothesized that radiation would lower the tumor burdens, decrease the number/function of regulatory cells in the tumor environment, and release products of tumor cells that could be acquired by intratumoral injected immature dendritic cells (iDC).These results demonstrate the safety and effectiveness of this multimodality strategy combining immunotherapy and IMRT in patients with advanced malignancies.

View Article: PubMed Central - PubMed

Affiliation: Hasumi International Research Foundation, Tokyo Research Center, 1-44-6 Asagaya-kita, Suginami- ku, Tokyo 166-0001, Japan. dmann001@umaryland.edu.

ABSTRACT
Successful cancer immunotherapy is confounded by the magnitude of the tumor burden and the presence of immunoregulatory elements that suppress an immune response. To approach these issues, 26 patients with advanced treatment refractory cancer were enrolled in a safety/feasibility study wherein a conventional treatment modality, intensity modulated radiotherapy (IMRT), was combined with dendritic cell-based immunotherapy. We hypothesized that radiation would lower the tumor burdens, decrease the number/function of regulatory cells in the tumor environment, and release products of tumor cells that could be acquired by intratumoral injected immature dendritic cells (iDC). Metastatic lesions identified by CT (computed tomography) were injected with autologous iDC combined with a cytokine-based adjuvant and KLH (keyhole limpet hemocyanin), followed 24 h later by IV-infused T-cells expanded with anti-CD3 and IL-2 (AT). After three to five days, each of the injected lesions was treated with fractionated doses of IMRT followed by another injection of intratumoral iDC and IV-infused AT. No toxicity was observed with cell infusion while radiation-related toxicity was observed in seven patients. Five patients had progressive disease, eight demonstrated complete resolution at treated sites but developed recurrent disease at other sites, and 13 showed complete response at various follow-up times with an overall estimated Kaplan-Meier disease-free survival of 345 days. Most patients developed KLH antibodies supporting our hypothesis that the co-injected iDC are functional with the capacity to acquire antigens from their environment and generate an adaptive immune response. These results demonstrate the safety and effectiveness of this multimodality strategy combining immunotherapy and IMRT in patients with advanced malignancies.

No MeSH data available.


Related in: MedlinePlus