In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study.
OBJECTIVE
Combining tumor antigens with an immunostimulant can induce the immune system to specifically eliminate cancer cells. Generally, this combination is accomplished in an ex vivo, customized manner. In a preclinical lymphoma model, intratumoral injection of a Toll-like receptor 9 (TLR9) agonist induced systemic antitumor immunity and cured large, disseminated tumors.


METHODS
We treated 15 patients with low-grade B-cell lymphoma using low-dose radiotherapy to a single tumor site and-at that same site-injected the C-G enriched, synthetic oligodeoxynucleotide (also referred to as CpG) TLR9 agonist PF-3512676. Clinical responses were assessed at distant, untreated tumor sites. Immune responses were evaluated by measuring T-cell activation after in vitro restimulation with autologous tumor cells.


RESULTS
This in situ vaccination maneuver was well-tolerated with only grade 1 to 2 local or systemic reactions and no treatment-limiting adverse events. One patient had a complete clinical response, three others had partial responses, and two patients had stable but continually regressing disease for periods significantly longer than that achieved with prior therapies. Vaccination induced tumor-reactive memory CD8 T cells. Some patients' tumors were able to induce a suppressive, regulatory phenotype in autologous T cells in vitro; these patients tended to have a shorter time to disease progression. One clinically responding patient received a second course of vaccination after relapse resulting in a second, more rapid clinical response.


CONCLUSIONS
In situ tumor vaccination with a TLR9 agonist induces systemic antilymphoma clinical responses. This maneuver is clinically feasible and does not require the production of a customized vaccine product.
Brody
Joshua D
JD
269 Campus Dr - CCSR rm 1105, Stanford, CA 94305, USA.
Ai
Weiyun Z
WZ
Czerwinski
Debra K
DK
Torchia
James A
JA
Levy
Mia
M
Advani
Ranjana H
RH
Kim
Youn H
YH
Hoppe
Richard T
RT
Knox
Susan J
SJ
Shin
Lewis K
LK
Wapnir
Irene
I
Tibshirani
Robert J
RJ
Levy
Ronald
R
D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000276:immunology*; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D015552:Injections, Intralesional; D016015:Logistic Models; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000532:radiotherapy; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000276:immunology*; D010641:Phenotype; D011379:Prognosis; D016016:Proportional Hazards Models; D012074:Remission Induction; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000276:immunology*; D016896:Treatment Outcome
D019496:Cancer Vaccines; D009838:Oligodeoxyribonucleotides; C483020:ProMune; D051217:Toll-Like Receptor 9