Table 1: Selected approaches to tumor immunotherapy.

ApproachTargetAgentImmune modulation of hostPhase of experimentationMain findings

VaccinationGliomaTumor-cell lysate pulsed DCsPhase I clinical trial completed (NCT00576537)T-cell responses, detection of infiltrating T cells in recurrent glioma associated with prolonged survival [210]

VaccinationAdenocarcinoma 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, CEARecombinant Vaccinia and Fowlpox virus (PANVAC) encoding MUC-1 and CEAGM-CSF treatment during vaccinationsPhase II clinical trial ongoing (NCT00179309)Induction of T-cell specific immune responses [211]

VaccinationAdenocarcinoma of the prostate expressing “TCRγ Alternative Reading frame Protein”Vaccination with TARP peptidesUse of Montanide ISA-51 VG as adjuvant and concomitant GM-CSF treatmentPreclinical study and phase-I clinical trial ongoing (NCT00908258)Preclinical study demonstrated induction of T-cell-specific immune responses [212]

VaccinationMelanomaMART-1-, gp100-, tyrosinase- peptidesSubcutaneous injection of IFN-α2b and/or GM-CSFPhase 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]

VaccinationMelanomaMAGE-3.A1 peptide and/or NA17.A2 peptideperitumoral injection of IL-2, IFN-α and GM-CSF, and topical application of imiquimodPhase I/II clinical trial ongoing (NCT01191034)

VaccinationCEA expressing cancersEx vivo activation of DCs using recombinant Fowlpox virus encoding CEADenileukin diftitox-mediated depletion of TregsPhase I clinical trial ongoing (NCT00128622)Increased T-cell responses to CEA-positive target cells [171]

VaccinationMelanomaTyrosinase/gp100/MART-1 PeptidesUse 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]
Melanomagp100 peptidesVaccination 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]

VaccinationGliomaTumor cell lysate pulsed dendritic cellsTLR agonist ImiquimodPhase II clinical trial ongoing (NCT01204684)Improved survival of a subset of glioma patients [168]

VaccinationLeukemiaAutologous leukemia cellsAutologous skin fibroblasts transduced with recombinant adenoviral vectors encoding CD40L and IL-2Phase I/II clinical trial ongoing (NCT00058799)Observed immune responses including antibodies against leukemic blasts, prolonged survival time of patients [215]

TLR agonist monotherapyTLR 9 in MelanomaCpG 7909Phase 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 monotherapyTLR7 in basal cell carcinomaImiquimodPhase II clinical trial completed (NCT00189241)FDA approved for treatment of superficial basal cell carcinoma [167]

Immunotoxin monotherapyRenal cell carcinomaDenileukin diftitox (IL-2-diphteria toxin fusion protein)Complementary IL-2 treatmentPhase I clinical trial completed (NCT00278369)Partial depletion of Tregs, no increase in antitumor response rates when compared to controls [216]

TGFβ antisense (AS) oligonucleotide monotherapyTGFβ expression in patients with recurrent high grade gliomaTGFβ AS (AP-12009, Trabedersen)Local depletion of TGFβPhase IIb clinical trial completed (NCT00431561)Well tolerated, increased median survival time of patients [195]

Anti-TGFβ antibody monotherapyTGFβ expression in patients with renal cell carcinoma, melanomaBlocking anti-TGFβ antibody (GC-1008)Systemic depletion of TGFβPhase I clinical trial safety and efficacy study (NCT00356460)

Anti-PD-1 antibody monotherapyRefractory or relapsed malignancies (solid tumors)Anti-PD-1 antibody (MDX-1106)Blocking extrinsic self-regulatory pathways of T cellsPhase I clinical trial (NCT00441337)Complete and partial responses, induction of inflammatory colitis [179]

Anti-CD137/4-1BB monotherapyMelanomaAnti-CD137/4-1BB antibody (BMS-663513)Systemic co-stimulation of T cellsPhase II clinical trial completed (NCT00612664) [188]

Adoptive cell therapyMelanomaEx vivo expanded TILsChemotherapy-mediated lymphodepletion prior infusion of TILs, high dose IL-2 treatmentPhase 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 therapyMelanomaEx vivo expanded TILs enriched for CD8* T cells genetically engineered to express IL-12Chemotherapy-mediated lymphodepletion prior infusion of TILsPhase I/II clinical trial ongoing (NCT01236573)

Genetic manipulation of T cells for immune therapyNeuroblastoma cells expressing L1-CAM (CD171)Ex vivo generated anti-CD171-CAR engineered T cellsPhase 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 immunotherapyNon-Hodgkin lymphoma and mantle cell lymphomaEx vivo generated anti-CD20-CAR engineered T cellsLow dose IL-2 treatmentPhase 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 immunotherapyMetastatic cancers that express NY-ESO-1Ex vivo generated anti-NY ESO-1 TCR-gene engineered T cellsChemotherapy-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 treatmentPhase II clinical trial ongoing (NCT00670748)

Genetic manipulation of T cells for immunotherapyB-cell malignancies with expression of CD19Ex vivo generated anti-CD19-CAR engineered T cellsChemotherapy-mediated lymphodepletion prior infusion of TILs, high dose IL-2 treatmentPhase 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 immunotherapyMetastatic cancers expressing Her2Ex vivo generated anti-Her2-CAR engineered T cellsChemotherapy-mediated lymphodepletion prior infusion of modified T cells, IL-2 treatmentPhase I/II clinical trial completed (NCT00924287)

ClinicalTrials.gov identifier, Eastern Cooperative Oncology Group (ECOG) identifier, and FDA-authorized pilot clinical study identifier are given in brackets.