Idiotype Vaccination in Human Myeloma: Generation of Tumor-Specific Immune Responses After High-Dose Chemotherapy

Blood ◽  
1999 ◽  
Vol 94 (2) ◽  
pp. 673-683 ◽  
Author(s):  
Massimo Massaia ◽  
Paolo Borrione ◽  
Silvano Battaglio ◽  
Sara Mariani ◽  
Eloise Beggiato ◽  
...  
Keyword(s):  
Immune Responses ◽  
Residual Disease ◽  
Interleukin 2 ◽  
Keyhole Limpet Hemocyanin ◽  
High Dose Chemotherapy ◽  
Outpatient Setting ◽  
Delayed Type Hypersensitivity ◽  
High Dose ◽  
Gm Csf ◽  
Macrophage Colony

Igs contain unique portions, collectively termed idiotypes (Id), that can be recognized by the immune system. Id expressed by tumor cells in B-cell malignancies can be regarded as tumor-specific antigens and a target for vaccine immunotherapy. We have started a vaccination trial in multiple myeloma (MM) using Id-specific proteins conjugated to keyhole limpet hemocyanin (KLH) as immunogens and low doses of subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2 (IL-2) as immunoadjuvants. Twelve patients who had previously been treated with high-dose chemotherapy followed by peripheral blood progenitor cell (PBPC) transplantation entered this study from August 1995 to January 1998. All patients were in first remission at the time of vaccination. They received subcutaneous injections of Id vaccines and immunoadjuvants in an outpatient setting. The generation of Id-specific T-cell proliferative responses was documented in 2 patients, whereas a positive Id-specific delayed-type hypersensitivity (DTH) reaction was observed in 8 of the 10 patients studied. DTH specificity was confirmed in 1 patient by investigating the reactivity to synthetic peptides derived from the VDJ sequence of the tumor-specific Ig heavy chain. None of the patients generated soluble immune responses to Id, whereas the generation of soluble and cellular immune responses to KLH was observed in 100% and 80%, respectively. Eleven patients completed the treatment, whereas 1 patient failed to finish owing to progression of disease. Freedom from disease progression (FFDP), measured from the date of first Id/KLH injection to the date of first treatment after vaccination or last follow-up, ranged from 9 to 36 months. These data indicate that the immune competence status of MM patients is still susceptible to specific immunization after high-dose chemotherapy and PBPC transplantation. It remains to be determined whether generation of Id-specific immune responses can reduce the relapse rate of patients with minimal residual disease.

Idiotype Vaccination in Human Myeloma: Generation of Tumor-Specific Immune Responses After High-Dose Chemotherapy

Blood ◽  
1999 ◽  
Vol 94 (2) ◽  
pp. 673-683 ◽  
Author(s):  
Massimo Massaia ◽  
Paolo Borrione ◽  
Silvano Battaglio ◽  
Sara Mariani ◽  
Eloise Beggiato ◽  
...  
Keyword(s):  
Immune Responses ◽  
Residual Disease ◽  
Interleukin 2 ◽  
Keyhole Limpet Hemocyanin ◽  
High Dose Chemotherapy ◽  
Outpatient Setting ◽  
Delayed Type Hypersensitivity ◽  
High Dose ◽  
Gm Csf ◽  
Macrophage Colony

Abstract Igs contain unique portions, collectively termed idiotypes (Id), that can be recognized by the immune system. Id expressed by tumor cells in B-cell malignancies can be regarded as tumor-specific antigens and a target for vaccine immunotherapy. We have started a vaccination trial in multiple myeloma (MM) using Id-specific proteins conjugated to keyhole limpet hemocyanin (KLH) as immunogens and low doses of subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2 (IL-2) as immunoadjuvants. Twelve patients who had previously been treated with high-dose chemotherapy followed by peripheral blood progenitor cell (PBPC) transplantation entered this study from August 1995 to January 1998. All patients were in first remission at the time of vaccination. They received subcutaneous injections of Id vaccines and immunoadjuvants in an outpatient setting. The generation of Id-specific T-cell proliferative responses was documented in 2 patients, whereas a positive Id-specific delayed-type hypersensitivity (DTH) reaction was observed in 8 of the 10 patients studied. DTH specificity was confirmed in 1 patient by investigating the reactivity to synthetic peptides derived from the VDJ sequence of the tumor-specific Ig heavy chain. None of the patients generated soluble immune responses to Id, whereas the generation of soluble and cellular immune responses to KLH was observed in 100% and 80%, respectively. Eleven patients completed the treatment, whereas 1 patient failed to finish owing to progression of disease. Freedom from disease progression (FFDP), measured from the date of first Id/KLH injection to the date of first treatment after vaccination or last follow-up, ranged from 9 to 36 months. These data indicate that the immune competence status of MM patients is still susceptible to specific immunization after high-dose chemotherapy and PBPC transplantation. It remains to be determined whether generation of Id-specific immune responses can reduce the relapse rate of patients with minimal residual disease.

scholarly journals Vaccination of Cattle with Mycobacterium bovis Culture Filtrate Proteins and Interleukin-2 for Protection against Bovine Tuberculosis

2000 ◽  
Vol 68 (10) ◽  
pp. 5809-5815 ◽  
Author(s):  
D. Neil Wedlock ◽  
Bridget Vesosky ◽  
Margot A. Skinner ◽  
Geoffrey W. de Lisle ◽  
Ian M. Orme ◽  
...  
Keyword(s):  
Immune Responses ◽  
Mycobacterium Bovis ◽  
Culture Filtrate ◽  
Lipid A ◽  
Interleukin 2 ◽  
Delayed Type Hypersensitivity ◽  
Control Group ◽  
High Dose ◽  
Monophosphoryl Lipid A ◽  
Culture Filtrate Proteins

ABSTRACT In this study vaccines prepared from culture filtrate proteins (CFP) of Mycobacterium bovis and interleukin-2 (IL-2) were tested in cattle for their capacity to stimulate immune responses and to protect against an intratracheal challenge with virulent M. bovis. Nine groups of cattle were vaccinated with combinations of different doses of CFP and bovine IL-2 mixed with a monophosphoryl lipid A (MPL) adjuvant. An additional group was vaccinated withM. bovis BCG. Immune responses in CFP–IL-2-vaccinated animals differed from those seen in BCG-vaccinated animals by inducing high antigen-specific antibody responses and low levels of gamma interferon and IL-2 released from purified protein derivative-stimulated whole-blood cultures. In a concurrent experiment, additional animals were added to the high-dose CFP–IL-2, MPL control, and BCG groups and these expanded groups of animals were challenged intratracheally with virulent M. bovis. Although the lung lesion scores were significantly lower for both the CFP–IL-2-and BCG-vaccinated groups compared to the MPL control group, the overall level of protection was greatest for the BCG-vaccinated animals. There were more animals with extrathoracic spread of disease in the CFP–IL-2 group than in the other groups. While vaccination of cattle withM. bovis CFP gave an encouraging reduction in tuberculous lesions and did not induce a delayed-type hypersensitivity response to PPD, future CFP vaccines must prevent any extrathoracic spread of disease.

Anti-GD2 monoclonal antibody 3F8 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) for primary refractory neuroblastoma (NB) in bone marrow (BM)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9502-9502 ◽  
Author(s):  
B. H. Kushner ◽  
K. Kramer ◽  
S. Modak ◽  
N. V. Cheung
Keyword(s):  
Complete Response ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Post Transplant ◽  
Gm Csf ◽  
Group 3 ◽  
Macrophage Colony Stimulating Factor ◽  
Group 2 ◽  
Macrophage Colony

9502 Background: Despite high-dose chemotherapy, NB in BM often persists and forebodes death. Methods: 3F8/GM- CSF was used in 63 patients (pts) with NB in BM by morphology and/or metaiodobenzylguanidine (MIBG) scan, no prior progressive disease or immunotherapy, and no soft tissue NB; 35 (56%) of the pts had received second-line therapy and 24 (38%) were post-transplant. Treatment was repeated if human anti-mouse antibody (HAMA) titer was low. Results: Of 30 pts with NB in BM but normal MIBG scans (Group 1), 25 (83%) had complete response (CR) after cycle 1 (n=17), cycle 2 (n=5), or cycle 3, 6, or 7 (one pt each), including 13/16 post-transplant pts. Among 15 pts with NB in BM and abnormal MIBG scans (Group 2), 12 (80%) had CR in BM after cycle 1 (n=5), cycle 2 (n=4), cycle 4 (n=2), or cycle 9 (n=1); MIBG scans normalized in 5/11 pts who had multiple abnormal MIBG(+) sites and in 4/4 pts who had one abnormal MIBG(+) site (irradiated in three pts). Of 18 pts who had abnormal MIBG scans but no NB seen in BM tests (Group 3), 14 (78%) had CR or near CR, including eight whose MIBG(+) sites were irradiated. Early HAMA limited treatment in 19 pts, but was prevented by high-dose cyclophosphamide. CR continues in 12 pts (five never transplanted) with long follow-up (20+ -to- 146+ months) and in 10 pts with short follow-up. The only common toxicities of this outpatient treatment were pain and hives; there were no long-term toxicities. Conclusions: 3F8/GM-CSF is well tolerated, achieves a high CR rate against primary refractory NB in BM (including post-transplant), and may prolong disease control in non- transplanted pts. Further experience will show whether it ought to be used for consolidative therapy in place of myeloablative cytoreduction. No significant financial relationships to disclose.

scholarly journals Cytokine Working Group Study of Lymphodepleting Chemotherapy, Interleukin-2, and Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Metastatic Melanoma: Clinical Outcomes and Peripheral-Blood Cell Recovery

2010 ◽  
Vol 28 (7) ◽  
pp. 1196-1202 ◽  
Author(s):  
Krishna S. Gunturu ◽  
Kenneth R. Meehan ◽  
Todd A. Mackenzie ◽  
Todd S. Crocenzi ◽  
David McDermott ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Interleukin 2 ◽  
High Dose ◽  
Memory Cells ◽  
Colony Stimulating Factor ◽  
Regulatory Cells ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Purpose Recovery of lymphocyte populations after lymphocyte depletion is implicated in therapeutic immune pathways in animal models and in patients with cancer. We sought to evaluate the effects of chemotherapy-induced lymphodepletion followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) and high-dose interleukin-2 (IL-2) therapy on clinical response and the recovery of lymphocyte subcompartments in patients with metastatic melanoma. Patients and Methods This was a two-stage phase II trial design. Patients with measurable metastatic melanoma were treated with intravenous cyclophosphamide (60 mg/kg, days 1 and 2) and fludarabine (25 mg/m2, day 3 through 7) followed by two 5-day courses of intravenous high-dose bolus IL-2 (600,000 U/kg; days 8 through 12 and 21 through 25). GM-CSF (250 μg/m2/d beginning day 8) was given until granulocyte recovery. Lymphocyte recovery profiles were determined by flow cytometric phenotyping at regular intervals, and clinical outcome was assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Results The trial was stopped at the end of stage 1 with four of 18 objective responses noted. Twelve patients had detailed lymphocyte subcompartments evaluated. After lymphodepletion, we observed an induction of regulatory cells (CD4+ T regulatory cells; CD8+ T suppressor cells) and of T memory cells (CD8+ T central memory cells; T effector memory RA+ cells). Expansion of circulating melanoma-specific CD8+ cells was observed in one of four HLA-A2-positive patients. Conclusion Chemotherapy-induced lymphodepletion modulates the homeostatic repopulation of the lymphocyte compartment and influences recovering lymphocyte subpopulations. Clinical activity seems similar to standard high-dose aldesleukin alone.

Disposition of recombinant human granulocyte-macrophage colony- stimulating factor in patients receiving high-dose chemotherapy and autologous bone marrow support

Blood ◽  
1992 ◽  
Vol 80 (5) ◽  
pp. 1135-1140 ◽  
Author(s):  
WP Petros ◽  
J Rabinowitz ◽  
AR Stuart ◽  
CJ Gilbert ◽  
Y Kanakura ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Autologous Bone Marrow ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Autologous Bone ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) produces dose-related therapeutic and toxic effects; however, relationships between its pharmacokinetics and pharmacodynamics have not been extensively evaluated. The following studies were undertaken to investigate patterns in the disposition of rHuGM-CSF administered after high-dose chemotherapy (cyclophosphamide, cisplatin, carmustine) and autologous bone marrow support. Continuous 14 or 21 day intravenous infusions or daily 4-hour infusions were studied at doses of 1.2 to 19.2 micrograms/kg/d. GM-CSF was measured by an enzyme-linked immunosorbent assay from serum and urine samples collected throughout drug administration. Pharmacokinetic parameters were determined by compartmental (4-hour infusions) or noncompartmental methods (continuous infusions). GM-CSF was rapidly eliminated from the serum. Average systemic exposure increased with dose, although wide interpatient variability was evident. Approximately one half of the patients receiving continuous infusions demonstrated increasing GM-CSF clearance that corresponded to the appearance of white blood cells in the periphery. Conversely, clearance decreased in those experiencing renal dysfunction during the infusion. The percentage of a GM-CSF dose found in 24-hour urine collections was substantially reduced in the latter group. A subset of patients who developed renal dysfunction also experienced significant hypotension. Rapidly increasing serum GM-CSF concentrations corresponded to the hypotensive episodes. GM-CSF serum concentration monitoring may be useful for evaluation of therapeutic and toxic effects in patients receiving high-dose chemotherapy with autologous bone marrow support.

Lymphodepletion with high-dose interleukin-2 (IL-2) and granulocyte macrophage-colony stimulating factor (GM-CSF) in metastatic melanoma patients: An interim analysis

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8034-8034
Author(s):  
S. L. Ketchum ◽  
B. Cole ◽  
K. Margolin ◽  
D. McDermott ◽  
T. Crocenzi ◽  
...  
Keyword(s):  
T Cells ◽  
Metastatic Melanoma ◽  
Interleukin 2 ◽  
Subcutaneous Administration ◽  
Complete Response ◽  
High Dose ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Melanoma Patients ◽  
Macrophage Colony

8034 Background: Lymphocyte depletion followed by homeostatic recovery has been shown to break tumor-specific tolerance. We have initiated a clinical trial of chemotherapy-induced lymphodepletion followed by high-dose (HD) IL-2 + GM-CSF in metastatic melanoma (MM) patients (pts). Methods: Pts with PS 0–1, normal organ function and with measurable MM were treated with intravenous cyclophosphamide 60 mg/kg (day 1–2), fludarabine 25 mg/m2 (day 3–7) followed by two 5-day (d) courses of intravenous HD bolus IL-2 600,000 IU/kg (d 8–12 and 21–25) and daily subcutaneous administration of GM-CSF 250 mcg/m2 (d 8 until granulocyte recovery). Results: 8 pts are presently evaluable in this first stage of accrual to confirm safety and immunomodulation. A mean of 25/28 IL-2 doses were delivered. All pts experienced transient myelosuppression with ANC < 500 cells/mm3 for a median of 7d (range 5–11d) and platelets <50,000/mm3 for a median of 5.5 days (range 0–7d). Pts exhibited reversible capillary leak associated with high-dose IL-2. With the exception of myelosuppression, no grade 4 toxicities occurred. All pts experienced neutropenic fever and 2 developed line infections. CD4+/CD25high/CD62L+ T cells rebounded by d 14, peaked around d 28 and returned to baseline by d 85. CD8+/CD28- T cells recovered to levels lower than baseline for the first 28d but then showed persistent elevation through d 113. Skewing of T-cell populations based on TCR β chain expression was observed. One pt achieved complete response, 2 achieved partial responses, and 5 progressed. Conclusions: Lymphodepletion followed by high-dose IL-2 can be safely administered, affects immune reconstitution, and has activity in MM that may be useful as a platform for enhancing immunotherapeutic strategies. The trial continues to accrue in order to better estimate antitumor activity and immunomodulation. No significant financial relationships to disclose.

scholarly journals Disposition of recombinant human granulocyte-macrophage colony- stimulating factor in patients receiving high-dose chemotherapy and autologous bone marrow support

Blood ◽  
1992 ◽  
Vol 80 (5) ◽  
pp. 1135-1140
Author(s):  
WP Petros ◽  
J Rabinowitz ◽  
AR Stuart ◽  
CJ Gilbert ◽  
Y Kanakura ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Autologous Bone Marrow ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Autologous Bone ◽  
Macrophage Colony ◽  
Stimulating Factor

Recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) produces dose-related therapeutic and toxic effects; however, relationships between its pharmacokinetics and pharmacodynamics have not been extensively evaluated. The following studies were undertaken to investigate patterns in the disposition of rHuGM-CSF administered after high-dose chemotherapy (cyclophosphamide, cisplatin, carmustine) and autologous bone marrow support. Continuous 14 or 21 day intravenous infusions or daily 4-hour infusions were studied at doses of 1.2 to 19.2 micrograms/kg/d. GM-CSF was measured by an enzyme-linked immunosorbent assay from serum and urine samples collected throughout drug administration. Pharmacokinetic parameters were determined by compartmental (4-hour infusions) or noncompartmental methods (continuous infusions). GM-CSF was rapidly eliminated from the serum. Average systemic exposure increased with dose, although wide interpatient variability was evident. Approximately one half of the patients receiving continuous infusions demonstrated increasing GM-CSF clearance that corresponded to the appearance of white blood cells in the periphery. Conversely, clearance decreased in those experiencing renal dysfunction during the infusion. The percentage of a GM-CSF dose found in 24-hour urine collections was substantially reduced in the latter group. A subset of patients who developed renal dysfunction also experienced significant hypotension. Rapidly increasing serum GM-CSF concentrations corresponded to the hypotensive episodes. GM-CSF serum concentration monitoring may be useful for evaluation of therapeutic and toxic effects in patients receiving high-dose chemotherapy with autologous bone marrow support.

scholarly journals Immune Monitoring during Therapy Reveals Activitory and Regulatory Immune Responses in High-Risk Neuroblastoma

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2096
Author(s):  
Celina L. Szanto ◽  
Annelisa M. Cornel ◽  
Sara M. Tamminga ◽  
Eveline M. Delemarre ◽  
Coco C. H. de Koning ◽  
...  
Keyword(s):  
T Cells ◽  
High Risk ◽  
Nk Cells ◽  
Immune Cell ◽  
High Dose Chemotherapy ◽  
Immune Monitoring ◽  
High Dose ◽  
Effector Cells ◽  
Gm Csf ◽  
Immune Cell Subsets

Despite intensive treatment, including consolidation immunotherapy (IT), prognosis of high-risk neuroblastoma (HR-NBL) is poor. Immune status of patients over the course of treatment, and thus immunological features potentially explaining therapy efficacy, are largely unknown. In this study, the dynamics of immune cell subsets and their function were explored in 25 HR-NBL patients at diagnosis, during induction chemotherapy, before high-dose chemotherapy, and during IT. The dynamics of immune cells varied largely between patients. IL-2- and GM-CSF-containing IT cycles resulted in significant expansion of effector cells (NK-cells in IL-2 cycles, neutrophils and monocytes in GM-CSF cycles). Nonetheless, the cytotoxic phenotype of NK-cells was majorly disturbed at the start of IT, and both IL-2 and GM-CSF IT cycles induced preferential expansion of suppressive regulatory T-cells. Interestingly, proliferative capacity of purified patient T-cells was impaired at diagnosis as well as during therapy. This study indicates the presence of both immune-enhancing as well as regulatory responses in HR-NBL patients during (immuno)therapy. Especially the double-edged effects observed in IL-2-containing IT cycles are interesting, as this potentially explains the absence of clinical benefit of IL-2 addition to IT cycles. This suggests that there is a need to combine anti-GD2 with more specific immune-enhancing strategies to improve IT outcome in HR-NBL.

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