TY - JOUR
T1 - Cytokines produced by dendritic cells administered intratumorally correlate with clinical outcome in patients with diverse cancers
AU - Subbiah, Vivek
AU - Murthy, Ravi
AU - Hong, David S.
AU - Prins, Robert M.
AU - Hosing, Chitra
AU - Hendricks, Kyle
AU - Kolli, Deepthi
AU - Noffsinger, Lori
AU - Brown, Robert
AU - McGuire, Mary
AU - Fu, Siquing
AU - Piha-Paul, Sarina
AU - Naing, Aung
AU - Conley, Anthony P.
AU - Benjamin, Robert S.
AU - Kaur, Indreshpal
AU - Bosch, Marnix L.
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/8/15
Y1 - 2018/8/15
N2 - Purpose: Dendritic cells (DC) initiate adaptive immune responses through the uptake and presentation of antigenic material. In preclinical studies, intratumorally injected activated DCs (aDCs; DCVax-Direct) were superior to immature DCs in rejecting tumors from mice. Experimental Design: This single-arm, open-label phase I clinical trial evaluated the safety and efficacy of aDCs, administered intratumorally, in patients with solid tumors. Three dose levels (2 million, 6 million, and 15 million aDCs per injection) were tested using a standard 3 þ 3 dose-escalation trial design. Feasibility, immunogenicity, changes to the tumor microenvironment after direct injection, and survival were evaluated. We also investigated cytokine production of aDCs prior to injection. Results: In total, 39 of the 40 enrolled patients were evaluable. The injections of aDCs were well tolerated with no dose-limiting toxicities. Increased lymphocyte infiltration was observed in 54% of assessed patients. Stable disease (SD; best response) at week 8 was associated with increased overall survival. Increased secretion of interleukin (IL)-8 and IL12p40 by aDCs was significantly associated with survival (P ¼ 0.023 and 0.024, respectively). Increased TNFa levels correlated positively with SD at week 8 (P < 0.01). Conclusions: Intratumoral aDC injections were feasible and safe. Increased production of specific cytokines was correlated with SD and prolonged survival, demonstrating a link between the functional profile of aDCs prior to injection and patient outcomes.
AB - Purpose: Dendritic cells (DC) initiate adaptive immune responses through the uptake and presentation of antigenic material. In preclinical studies, intratumorally injected activated DCs (aDCs; DCVax-Direct) were superior to immature DCs in rejecting tumors from mice. Experimental Design: This single-arm, open-label phase I clinical trial evaluated the safety and efficacy of aDCs, administered intratumorally, in patients with solid tumors. Three dose levels (2 million, 6 million, and 15 million aDCs per injection) were tested using a standard 3 þ 3 dose-escalation trial design. Feasibility, immunogenicity, changes to the tumor microenvironment after direct injection, and survival were evaluated. We also investigated cytokine production of aDCs prior to injection. Results: In total, 39 of the 40 enrolled patients were evaluable. The injections of aDCs were well tolerated with no dose-limiting toxicities. Increased lymphocyte infiltration was observed in 54% of assessed patients. Stable disease (SD; best response) at week 8 was associated with increased overall survival. Increased secretion of interleukin (IL)-8 and IL12p40 by aDCs was significantly associated with survival (P ¼ 0.023 and 0.024, respectively). Increased TNFa levels correlated positively with SD at week 8 (P < 0.01). Conclusions: Intratumoral aDC injections were feasible and safe. Increased production of specific cytokines was correlated with SD and prolonged survival, demonstrating a link between the functional profile of aDCs prior to injection and patient outcomes.
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U2 - 10.1158/1078-0432.CCR-17-2707
DO - 10.1158/1078-0432.CCR-17-2707
M3 - Article
C2 - 30018119
AN - SCOPUS:85051716688
SN - 1078-0432
VL - 24
SP - 3845
EP - 3856
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -