Table 1.
Clinical trials and mouse studies of CpG-ODN alone or in combination with other modalities.
| Combination | ODN Class | Name of CpG (Route) | Phase | Object | N | Efficacy (%) |
IR (%) |
AEs | Authors [Ref] |
|---|---|---|---|---|---|---|---|---|---|
| CpG-ODN alone |
B(=Type K) | PF-3512676 [=CPG7909] (IV) |
P1 | R/R NHL | 23 | No clinical responses | IgG elevation in 5 pts | Anemia Thrombocytopenia Neutropenia Transient lymphopenia Dyspnea Chills/rigors Nausea/vomiting Fever Hypotension Fatigue Pain Intravenous catheter discomfort ALT increased Hyperglycemia Proteinuria |
Link, and Weiner et al. [134] |
| CpG + R | B(=Type K) | PF-3512676 [=CPG7909] (IV or SC) |
P1 | Relapsed CD20+ B-NHL | 50 | 12OR (24%) |
NA | Systemic flu-like syndromes #1–1, Fatigue or rigors Pyrexia Malaise Injection-site reactions #2–1 Neutropenia Pain in limbs Generalized pruritus Peripheral neuropathy Sjögren’s-like syndrome #3 |
Leonard, Link, and Weiner et al. [137] |
| CpG + R | B(=Type K) | 1018 ISS (SC) |
P1 | R/R FL | 20 | 6OR [1CRu+5PR] (32%)+ 13SD Median PFS in responding pts: 12 mos |
Induction of IFN-α/β—inducible genes | Allergic reaction #4 Headache Fatigue Atypical pneumonia |
Friedberg, et al. [138] |
| CpG + R | B(=Type K) | 1018 ISS (SC) |
P2 | R/R FL | 23 | 11OR [CR/CRu or PR] (48%) + 6SD (26%) Median PFS: 8.8 mos |
T-cell and MØ infiltration in injection sites IFN-γ—secretion increased from T cells in PB (25%) ADCC increased (35%) Increased expression of IFN-α/β-inducible genes (IFIT2, CXCL10, CCL2) (≥60%) Increased CXCL10 expression in PB in responders |
Fatigue Rituximab infusion reaction Erythema at the injection sites |
Friedberg, et al. [139] |
| CpG + αOX40 + αCTLA4 | B(=Type K) | CpG1826 (IT) |
mice | A20 tumor cells | NA | Immune protection from tumor re-challenge over 100 days | IFN-γ-producing, memory T cell increased Treg decreased |
NA | Houot and Levy et al. [140] |
| CpG + ibrutinib | B(=Type K) | CpG1826 (IT) |
mice | H11 and B3750 tumor cells | NA | Tumor regression in at the distant site | % increase in tumor-specific IFN-γ-producing, memory T cells | NA | Sagiv-Barfi and Levy et al. [141] |
| CpG + LD RT | B(=Type K) | PF-3512676 (IT) |
P1/2 | Relapsed low-grade B-NHL | 15 | 1CR, 2PRs | Induced CD137/4-1BB expression and increased intracellular IFN-γ, IL -2, and TNF in memory CD8+ T cells in PB Treg induction in PB and tumor |
Injection site reaction #2–2 Flu-like reactions Arthralgia Myalgia |
Brody and Levy et al. [32] |
| CpG + LD RT (2 Gy x 2) |
C | SD-101 (IT) |
P1/2 | Untreated iNHL | 29 | 26 reductions, including 1CR, 7PRs | Increased T cell and decreased Tfh and Treg in injected tumors | Flu-like systemic reactions #1–2 Myalgia Fever Nausea/vomiting Diarrhea Injection-site reaction #2–3 Neutropenia Confusion Decreased appetite Night sweating Thrombocytopenia |
Frank and Levy et al. [152] |
| CpG + RIT | B(=Type K) | PF-3512676 [=CPG7909] (IV) |
P1 | R/R CD20+B-NHL | 30 | 28OR (93%) 19CRs (63%) Median PFS: 43 mos DOR: 35 mos Median TTP: 40.5 mos |
Decrease in IL-10 and TNF-α and increase in IL-1β in serum | Reversible myelosuppression (due to RIT) Pain on bulk neck lymph node (after infusion of CpG 7909) |
Witzig and Weiner et al. [158] |
#1–1 Were comprised of fever, fatigue, and headache. #1–2 Consisted of malaise, chills, headache, fatigue, and fever. #2–1 Included erythema, pain, edema, pruritus, bruising, and indurations. #2–2 Included erythema, induration, and tenderness. #2–3 Included erythema, swelling, and pain. #3 Was composed of conjunctivitis and oral mucositis. #4 Included hives, rhinitis, rigors, chills, and dyspnea. Abbreviations: ODN, oligodeoxynucleotide; IR, immune response; AEs, adverse events; IV, intravenous; P1, phase 1 study; R/R, relapsed or refractory; NHL, non-Hodgkin lymphoma; IgG, immunologlobulin G; pts, patients; aPTT, activated partial thromboplastin time; ALT, alanine aminotransferase; R, rituximab; SC, subcutaneous; B-NHL, B-cell NHL; OR, overall response; NA, not available; FL, follicular lymphoma; CRu, unconfirmed complete response; PR, partial response; SD, stable disease; PFS, progression-free survival; mos, months; IFN, interferon; CR, complete response; MØ, macrophage; PB, peripheral blood; ADCC, antibody-dependent cell-mediated cytotoxicity; IFIT2, interferon-induced protein with tetratricopeptide repeats 2; CXCL10, C-X-C motif chemokine ligand 10; CCL2, C-C motif chemokine ligand 2; αOX40, anti-OX40 antibody; αCTLA4, anti-cytotoxic T-lymphocyte-associated protein 4 antibody; IT, intratumoral; Treg, regulatory T cells; LD, low-dose; RT, radiotherapy; IL, interleukin; TNF, tumor necrosis factor; iNHL, indolent non-Hodgkin lymphoma; Tfh, follicular helper T cells; auto DCs, autologous dendritic cells; RIT, radioimmunotherapy; DOR, duration of response; TTP; time to progression.