In vivo manipulation of Vgamma9Vdelta2 T cells with zoledronate and low-dose interleukin-2 for immunotherapy of advanced breast cancer patients.
The potent anti-tumour activities of gammadelta T cells have prompted the development of protocols in which gammadelta-agonists are administered to cancer patients. Encouraging results from small Phase I trials have fuelled efforts to characterize more clearly the application of this approach to unmet clinical needs such as metastatic carcinoma. To examine this approach in breast cancer, a Phase I trial was conducted in which zoledronate, a Vgamma9Vdelta2 T cell agonist, plus low-dose interleukin (IL)-2 were administered to 10 therapeutically terminal, advanced metastatic breast cancer patients. Treatment was well tolerated and promoted the effector maturation of Vgamma9Vdelta2 T cells in all patients. However, a statistically significant correlation of clinical outcome with peripheral Vgamma9Vdelta2 T cell numbers emerged, as seven patients who failed to sustain Vgamma9Vdelta2 T cells showed progressive clinical deterioration, while three patients who sustained robust peripheral Vgamma9Vdelta2 cell populations showed declining CA15-3 levels and displayed one instance of partial remission and two of stable disease, respectively. In the context of an earlier trial in prostate cancer, these data emphasize the strong linkage of Vgamma9Vdelta2 T cell status to reduced carcinoma progression, and suggest that zoledronate plus low-dose IL-2 offers a novel, safe and feasible approach to enhance this in a subset of treatment-refractory patients with advanced breast cancer.
Meraviglia
S
S
Dipartimento di Biopatologia e Metodologie Biomediche, Universita di Palermo, Palermo, Italy.
Eberl
M
M
Vermijlen
D
D
Todaro
M
M
Buccheri
S
S
Cicero
G
G
La Mendola
C
C
Guggino
G
G
D'Asaro
M
M
Orlando
V
V
Scarpa
F
F
Roberts
A
A
Caccamo
N
N
Stassi
G
G
Dieli
F
F
Hayday
A C
AC
D000276:Adjuvants, Immunologic / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000368:Aged; D001943:Breast Neoplasms / Q000097:blood / Q000276:immunology / Q000628:therapy*; D049109:Cell Proliferation / Q000187:drug effects; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D004164:Diphosphonates / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D018450:Disease Progression; D004950:Esterases / Q000378:metabolism; D005260:Female; D045782:Hemiterpenes / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008875:Middle Aged; D018396:Mucin-1 / Q000097:blood; D009943:Organophosphorus Compounds / Q000494:pharmacology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D012074:Remission Induction; D016879:Salvage Therapy; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D016896:Treatment Outcome; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism; D000077211:Zoledronic Acid
D000276:Adjuvants, Immunologic; D018925:Chemokines; D016207:Cytokines; D004164:Diphosphonates; D045782:Hemiterpenes; D007093:Imidazoles; D007376:Interleukin-2; D018396:Mucin-1; C115996:N-benzyloxy-carbonyl-lysine thiobenzyl; D009943:Organophosphorus Compounds; D016692:Receptors, Antigen, T-Cell, gamma-delta; C521523:T-cell receptor Vdelta2, human; C521522:T-cell receptor Vgamma9, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; C004809:isopentenyl pyrophosphate; D000077211:Zoledronic Acid; D007371:Interferon-gamma; D004950:Esterases; D017493:Leukocyte Common Antigens; D008239:Lysine