HER2 Support Group Forums - View Single Post - for Stage IVs running out of options, a vaccine trial with hopeful results

Rich66 · 11-12-2011, 01:00 PM

another immune approach that makes me wonder if continuation might give better results:

J Immunol. 2011 Nov 2. [Epub ahead of print]
Pilot Clinical Trial of Type 1 Dendritic Cells Loaded with Autologous Tumor Lysates Combined with GM-CSF, Pegylated IFN, and Cyclophosphamide for Metastatic Cancer Patients.

Alfaro C, Perez-Gracia JL, Suarez N, Rodriguez J, Fernandez de Sanmamed M, Sangro B, Martin-Algarra S, Calvo A, Redrado M, Agliano A, Gonzalez A, Rodriguez I, Bolaños E, Hervás-Stubbs S, Perez-Calvo J, Benito A, Peñuelas I, Vigil C, Richter J, Martinez-Forero I, Melero I.

LINK

Source

Gene Therapy and Hepatology Unit, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain;

Abstract

Twenty-four patients with metastatic cancer received two cycles of four daily immunizations with monocyte-derived dendritic cells (DC). DC were incubated with preheated autologous tumor lysate and subsequently with IFN-α, TNF-α, and polyinosinicolycytidylic acid to attain type 1 maturation. One DC dose was delivered intranodally, under ultrasound control, and the rest intradermally in the opposite thigh. Cyclophosphamide (day -7), GM-CSF (days 1-4), and pegIFN alpha-2a (days 1 and 8) completed each treatment cycle. Pretreatment with cyclophosphamide decreased regulatory T cells to levels observed in healthy subjects both in terms of percentage and in absolute counts in peripheral blood. Treatment induced sustained elevations of IL-12 in serum that correlated with the output of IL-12p70 from cultured DC from each individual. NK activity in peripheral blood was increased and also correlated with the serum concentration of IL-12p70 in each patient. Circulating endothelial cells decreased in 17 of 18 patients, and circulating tumor cells markedly dropped in 6 of 19 cases. IFN-γ-ELISPOT responses to DC plus tumor lysate were observed in 4 of 11 evaluated cases. Tracing DC migration with [(111)In] scintigraphy showed that intranodal injections reached deeper lymphatic chains in 61% of patients, whereas with intradermal injections a small fraction of injected DC was almost constantly shown to reach draining inguinal lymph nodes. Five patients experienced disease stabilization, but no objective responses were documented. This combinatorial immunotherapy strategy is safe and feasible, and its immunobiological effects suggest potential activity in patients with minimal residual disease. A randomized trial exploring this hypothesis is currently ongoing.

PMID:22048768 [PubMed - as supplied by publisher]

Especially in light of this:

J Immunol. 2011 Oct 15;187(8):4109-18. Epub 2011 Sep 9.
Chronic chemoimmunotherapy achieves cure of spontaneous murine mammary tumors via persistent blockade of posttherapy counter-regulation.

Rowswell-Turner RB, Harden JL, Nair RE, Gu T, Kilinc MO, Egilmez NK.

LINK

Source

Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214,USA.

Abstract

Intratumoral delivery of IL-12 and GM-CSF induces local and systemic antitumor CD8(+) T cell activation and tumor kill. However, the effector response is transient and is rapidly countered by CD4(+) Foxp3(+) T suppressor cell expansion. To determine whether depletion of the pre-existing T suppressor cell pool prior to treatment could diminish posttherapy regulatory cell resurgence, FVBneuN mice bearing advanced spontaneous mammary tumors were treated with cyclophosphamide (CY) 1 d before IL-12/GM-CSF therapy. Administration of CY mediated a significant delay in the post-IL-12/GM-CSF T suppressor cell rebound, resulting in a 7-fold increase in the CD8(+) CTL/T suppressor cell ratio, a 3-fold enhancement of CTL cytotoxicity, and an extension of the effector window from 3 to 7 d. In long-term therapy studies, chronic chemoimmunotherapy promoted a dramatic enhancement of tumor regression, resulting in complete cure in 44% of the mice receiving CY plus IL-12/GM-CSF. Tumor eradication in the chronic therapy setting was associated with the ability to repeatedly rescue and maintain cytotoxic CD8(+) T cell activity. These findings demonstrated that chronic administration of CY in conjunction with immune therapy enhances the initial induction of antitumor T effector cells and, more importantly, sustains their cytotoxic activity over the long-term via persistent blockade of homeostatic counter-regulation.

And the approach of using Cytoxan to suppress undesirable immune responses keeps coming up...making me wonder if the PANVAC trial could have done better with some Cy in the mix.

Maybe it would help Herceptin.

11-12-2011, 01:00 PM	#5
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: for Stage IVs running out of options, a vaccine trial with hopeful results another immune approach that makes me wonder if continuation might give better results: J Immunol. 2011 Nov 2. [Epub ahead of print] Pilot Clinical Trial of Type 1 Dendritic Cells Loaded with Autologous Tumor Lysates Combined with GM-CSF, Pegylated IFN, and Cyclophosphamide for Metastatic Cancer Patients. Alfaro C, Perez-Gracia JL, Suarez N, Rodriguez J, Fernandez de Sanmamed M, Sangro B, Martin-Algarra S, Calvo A, Redrado M, Agliano A, Gonzalez A, Rodriguez I, Bolaños E, Hervás-Stubbs S, Perez-Calvo J, Benito A, Peñuelas I, Vigil C, Richter J, Martinez-Forero I, Melero I. LINK Source Gene Therapy and Hepatology Unit, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain; Abstract Twenty-four patients with metastatic cancer received two cycles of four daily immunizations with monocyte-derived dendritic cells (DC). DC were incubated with preheated autologous tumor lysate and subsequently with IFN-α, TNF-α, and polyinosinicolycytidylic acid to attain type 1 maturation. One DC dose was delivered intranodally, under ultrasound control, and the rest intradermally in the opposite thigh. Cyclophosphamide (day -7), GM-CSF (days 1-4), and pegIFN alpha-2a (days 1 and 8) completed each treatment cycle. Pretreatment with cyclophosphamide decreased regulatory T cells to levels observed in healthy subjects both in terms of percentage and in absolute counts in peripheral blood. Treatment induced sustained elevations of IL-12 in serum that correlated with the output of IL-12p70 from cultured DC from each individual. NK activity in peripheral blood was increased and also correlated with the serum concentration of IL-12p70 in each patient. Circulating endothelial cells decreased in 17 of 18 patients, and circulating tumor cells markedly dropped in 6 of 19 cases. IFN-γ-ELISPOT responses to DC plus tumor lysate were observed in 4 of 11 evaluated cases. Tracing DC migration with [(111)In] scintigraphy showed that intranodal injections reached deeper lymphatic chains in 61% of patients, whereas with intradermal injections a small fraction of injected DC was almost constantly shown to reach draining inguinal lymph nodes. Five patients experienced disease stabilization, but no objective responses were documented. This combinatorial immunotherapy strategy is safe and feasible, and its immunobiological effects suggest potential activity in patients with minimal residual disease. A randomized trial exploring this hypothesis is currently ongoing. PMID:22048768 [PubMed - as supplied by publisher] Especially in light of this: J Immunol. 2011 Oct 15;187(8):4109-18. Epub 2011 Sep 9. Chronic chemoimmunotherapy achieves cure of spontaneous murine mammary tumors via persistent blockade of posttherapy counter-regulation. Rowswell-Turner RB, Harden JL, Nair RE, Gu T, Kilinc MO, Egilmez NK. LINK Source Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214,USA. Abstract Intratumoral delivery of IL-12 and GM-CSF induces local and systemic antitumor CD8(+) T cell activation and tumor kill. However, the effector response is transient and is rapidly countered by CD4(+) Foxp3(+) T suppressor cell expansion. To determine whether depletion of the pre-existing T suppressor cell pool prior to treatment could diminish posttherapy regulatory cell resurgence, FVBneuN mice bearing advanced spontaneous mammary tumors were treated with cyclophosphamide (CY) 1 d before IL-12/GM-CSF therapy. Administration of CY mediated a significant delay in the post-IL-12/GM-CSF T suppressor cell rebound, resulting in a 7-fold increase in the CD8(+) CTL/T suppressor cell ratio, a 3-fold enhancement of CTL cytotoxicity, and an extension of the effector window from 3 to 7 d. In long-term therapy studies, chronic chemoimmunotherapy promoted a dramatic enhancement of tumor regression, resulting in complete cure in 44% of the mice receiving CY plus IL-12/GM-CSF. Tumor eradication in the chronic therapy setting was associated with the ability to repeatedly rescue and maintain cytotoxic CD8(+) T cell activity. These findings demonstrated that chronic administration of CY in conjunction with immune therapy enhances the initial induction of antitumor T effector cells and, more importantly, sustains their cytotoxic activity over the long-term via persistent blockade of homeostatic counter-regulation. And the approach of using Cytoxan to suppress undesirable immune responses keeps coming up...making me wonder if the PANVAC trial could have done better with some Cy in the mix. Maybe it would help Herceptin.