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| Approach | Target | Agent | Immune modulation of host | Phase of experimentation | Main findings |
|
| Vaccination | Glioma | Tumor-cell lysate pulsed DCs | — | Phase I clinical trial completed (NCT00576537) | T-cell responses, detection of infiltrating T cells in recurrent glioma associated with prolonged survival [210] |
|
| Vaccination | Adenocarcinoma of the prostate expressing “prostatic acid phosphatase” (PAP) | DCs ex vivo primed with PAP-GM-CSF fusion protein (Sipuleucel T, FDA-approved for treatment of hormone-refractory prostate cancer) | — | Phase III clinical trial completed (NCT00065442) | Increased overall survival, but no increase in progression-free survival of patients [169] |
|
| Vaccination and chemotherapy (Doxetacel) | Breast cancer with expression of MUC-1, CEA | Recombinant Vaccinia and Fowlpox virus (PANVAC) encoding MUC-1 and CEA | GM-CSF treatment during vaccinations | Phase II clinical trial ongoing (NCT00179309) | Induction of T-cell specific immune responses [211] |
|
| Vaccination | Adenocarcinoma of the prostate expressing “TCRγ Alternative Reading frame Protein” | Vaccination with TARP peptides | Use of Montanide ISA-51 VG as adjuvant and concomitant GM-CSF treatment | Preclinical study and phase-I clinical trial ongoing (NCT00908258) | Preclinical study demonstrated induction of T-cell-specific immune responses [212] |
|
| Vaccination | Melanoma | MART-1-, gp100-, tyrosinase- peptides | Subcutaneous injection of IFN-α2b and/or GM-CSF | Phase II clinical trial completed (ECOG E1696) | Neither IFN-α2b nor GM-CSF improved immune responses, 35% of patients developed T-cell responses associated with prolonged median overall survival [213] |
|
| Vaccination | Melanoma | MAGE-3.A1 peptide and/or NA17.A2 peptide | peritumoral injection of IL-2, IFN-α and GM-CSF, and topical application of imiquimod | Phase I/II clinical trial ongoing (NCT01191034) | — |
|
| Vaccination | CEA expressing cancers | Ex vivo activation of DCs using recombinant Fowlpox virus encoding CEA | Denileukin diftitox-mediated depletion of Tregs | Phase I clinical trial ongoing (NCT00128622) | Increased T-cell responses to CEA-positive target cells [171] |
|
| Vaccination | Melanoma | Tyrosinase/gp100/MART-1 Peptides | Use of Montanide ISA-51 VG as adjuvant, treatment with anti-CTLA4 antibody (MDX-010) | Phase I/II clinical trial ongoing (NCT00028431) | T-cell reactivity against gp100 and MART-1. CTLA-4 antibody dose-related adverse autoimmune effects in skin and gastrointestinal tract [214] |
| Melanoma | gp100 peptides | Vaccination using incomplete Freund's adjuvant, treatment with anti-CTLA4 antibody (Ipilimumab) | Phase II clinical trial completed (NCT00094653) | Improved overall survival when applying Ipilimumab irrespective of gp100 vaccination, adverse immunological site effects [185] |
|
| Vaccination | Glioma | Tumor cell lysate pulsed dendritic cells | TLR agonist Imiquimod | Phase II clinical trial ongoing (NCT01204684) | Improved survival of a subset of glioma patients [168] |
|
| Vaccination | Leukemia | Autologous leukemia cells | Autologous skin fibroblasts transduced with recombinant adenoviral vectors encoding CD40L and IL-2 | Phase I/II clinical trial ongoing (NCT00058799) | Observed immune responses including antibodies against leukemic blasts, prolonged survival time of patients [215] |
|
| TLR agonist monotherapy | TLR 9 in Melanoma | CpG 7909 | — | Phase II clinical trial completed (NCT00070642) | Increased frequencies of T cells reactive against target cells expressing melanoma-associated-antigens in sentinel lymph nodes [166] |
|
| TLR agonist monotherapy | TLR7 in basal cell carcinoma | Imiquimod | — | Phase II clinical trial completed (NCT00189241) | FDA approved for treatment of superficial basal cell carcinoma [167] |
|
| Immunotoxin monotherapy | Renal cell carcinoma | Denileukin diftitox (IL-2-diphteria toxin fusion protein) | Complementary IL-2 treatment | Phase I clinical trial completed (NCT00278369) | Partial depletion of Tregs, no increase in antitumor response rates when compared to controls [216] |
|
| TGFβ antisense (AS) oligonucleotide monotherapy | TGFβ expression in patients with recurrent high grade glioma | TGFβ AS (AP-12009, Trabedersen) | Local depletion of TGFβ | Phase IIb clinical trial completed (NCT00431561) | Well tolerated, increased median survival time of patients [195] |
|
| Anti-TGFβ antibody monotherapy | TGFβ expression in patients with renal cell carcinoma, melanoma | Blocking anti-TGFβ antibody (GC-1008) | Systemic depletion of TGFβ | Phase I clinical trial safety and efficacy study (NCT00356460) | — |
|
| Anti-PD-1 antibody monotherapy | Refractory or relapsed malignancies (solid tumors) | Anti-PD-1 antibody (MDX-1106) | Blocking extrinsic self-regulatory pathways of T cells | Phase I clinical trial (NCT00441337) | Complete and partial responses, induction of inflammatory colitis [179] |
|
| Anti-CD137/4-1BB monotherapy | Melanoma | Anti-CD137/4-1BB antibody (BMS-663513) | Systemic co-stimulation of T cells | Phase II clinical trial completed (NCT00612664) [188] | — |
|
| Adoptive cell therapy | Melanoma | Ex vivo expanded TILs | Chemotherapy-mediated lymphodepletion prior infusion of TILs, high dose IL-2 treatment | Phase II clinical trial ongoing (NCT00513604) | Objective clinical responses, in some cases durable complete responses, toxic side effects after chemotherapy and high IL-2 doses [174, 176] |
|
| Adoptive cell therapy | Melanoma | Ex vivo expanded TILs enriched for CD8* T cells genetically engineered to express IL-12 | Chemotherapy-mediated lymphodepletion prior infusion of TILs | Phase I/II clinical trial ongoing (NCT01236573) | — |
|
| Genetic manipulation of T cells for immune therapy | Neuroblastoma cells expressing L1-CAM (CD171) | Ex vivo generated anti-CD171-CAR engineered T cells | — | Phase I/II clinical trial completed (BB-IND#9149, FDA) | Weak tumor responses and limited persistence of CD171-CAR [201] |
|
| Genetic manipulation of T cells for immunotherapy | Non-Hodgkin lymphoma and mantle cell lymphoma | Ex vivo generated anti-CD20-CAR engineered T cells | Low dose IL-2 treatment | Phase I/II clinical trial completed (NCT00012207) | No side effects, regression of tumors, persistence of modified T cells for 9 weeks [202] |
|
| Genetic manipulation of T cells for immunotherapy | Metastatic cancers that express NY-ESO-1 | Ex vivo generated anti-NY ESO-1 TCR-gene engineered T cells | Chemotherapy-mediated lymphodepletion prior infusion of modified T cells. Modified T cells are further stimulated using ALVAC–ESO-1 vaccine, G-CSF and high dose IL-2 treatment | Phase II clinical trial ongoing (NCT00670748) | — |
|
| Genetic manipulation of T cells for immunotherapy | B-cell malignancies with expression of CD19 | Ex vivo generated anti-CD19-CAR engineered T cells | Chemotherapy-mediated lymphodepletion prior infusion of TILs, high dose IL-2 treatment | Phase I/II clinical trial ongoing (NCT00924326) | Regression of B-cell lymphoma and elimination of B-cell precursors in patients [203] |
|
| Genetic manipulation of T cells for immunotherapy | Metastatic cancers expressing Her2 | Ex vivo generated anti-Her2-CAR engineered T cells | Chemotherapy-mediated lymphodepletion prior infusion of modified T cells, IL-2 treatment | Phase I/II clinical trial completed (NCT00924287) | — |
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