Developing a rational tumor vaccine therapy for renal cell carcinoma: immune yin and yang.
In patients with progressive malignancy, the natural balance between proinflammatory (Yang) and inhibitory (regulatory or Yin) immune pathways is disrupted and favors cancer-specific immune suppression. Therapy with interleukin 2 (IL-2) can mobilize immune effector cells that recognize and destroy cancer. High-dose IL-2 is the only therapy that has consistently induced complete durable remissions in patients with metastatic renal cell carcinoma (RCC) but only in a few of them. The lack of benefit in most metastatic RCC patients is likely due to the ineffective manipulation of other immune circuits critical in regulating tumor cytotoxic pathways. The limited clinical activity of IL-2, RCC vaccines, and other immune therapies to date leads us to postulate that effective clinical treatment strategies will need to simultaneously enhance proinflammatory pathways and disrupt regulatory pathways. We present preliminary studies in RCC patients to highlight the complexity of the regulatory pathways and our approach to shifting the balance of proinflammatory and regulatory immune pathways using dendritic cell-tumor lysate vaccine followed by cytokine therapy.
Ernstoff
Marc S
MS
Medical Oncology Immunotherapy Group, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA. Marc.S.Emstoff@Hitchcock.org
Crocenzi
Todd S
TS
Seigne
John D
JD
Crosby
Nancy A
NA
Cole
Bernard F
BF
Fisher
Jan L
JL
Uhlenhake
Jill C
JC
Mellinger
Diane
D
Foster
Cathy
C
Farnham
Conrad J
CJ
Mackay
Kathleen
K
Szczepiorkowski
Zbigniew M
ZM
Webber
Susan M
SM
Schned
Alan R
AR
Harris
Robert D
RD
Barth
Richard J
RJ
Heaney
John A
JA
Noelle
Randolph J
RJ
D019496:Cancer Vaccines / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000628:therapy*; D016207:Cytokines / Q000627:therapeutic use; D003713:Dendritic Cells / Q000378:metabolism; D006801:Humans; D007107:Immune System; D007249:Inflammation; D007376:Interleukin-2 / Q000378:metabolism / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000628:therapy; D009362:Neoplasm Metastasis; D013997:Time Factors; D016896:Treatment Outcome
D019496:Cancer Vaccines; D016207:Cytokines; D007376:Interleukin-2