Featured Poster Abstract 84: CD8 T cell-mediated immune responses are critical to the increased efficacy of Doxil in BRCA1 deficient tumors Gina Mantia-Smaldone,
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Featured Poster Abstract 84:
CD8 T cell-mediated immune responses are critical to the increased efficacy of Doxil in
BRCA1 deficient tumors
Gina Mantia-Smaldone, Victoria Gamerman, Phyllis Gimotty, Regina Loomis, Lukas Ronner, Christopher Morse, Sandra Orsulic,
Stephen Rubin, George Coukos, Sarah Adams
BRCA-deficient tumors are vulnerable to the immunomodulatory effects of Doxil
• 56% of women with recurrent BRCA-associated ovarian cancer demonstrated a response to Doxil1
• In addition to causing DNA damage, Doxil increases the vulnerability of ovarian cancer cells to T cell attack
• Immunophenotypic changes in response to Doxil are more pronounced in BRCA-/- cells
• BRCA-/- tumors recruit higher numbers of T cells after Doxil exposure
• We hypothesized that the immunogenicity of BRCA-/- tumors contributes to the improved clinical response to Doxil among women with hereditary ovarian cancer
• The role of T cells in tumor clearance following exposure to Doxil was tested using a murine BRCA1-/- ovarian cancer model 1Adams SF et al, Gynecol Oncol 2011
Higher numbers of CD3+ Tumor Infiltrating Lymphocytes are present in murine BRCA1 -
tumors following Doxil therapy
0
20
40
60
80
100
low CD3 high CD3
Perc
ent
Control
Doxil
Endpoint: Weight ≥30 grams
Antibody
-7 -6 -5 0 3 10 17Experimental Day
Doxil
Tumor Innoculation
Antibody q3-4d
Doxil Doxil Endpoint: Weight ≥30 grams
Antibody
-7 -6 -5 0 3 10 17Experimental Day
Doxil
Tumor Innoculation
Antibody q3-4d
Doxil DoxilEvaluated in a cohort of 23 women with BRCA mutations and 41 women with sporadic cancer treated at three institutions between 2000-2010 for recurrent cancer. The response to Doxil was associated with a significant improval in overall survival
Doxil increased intratumoral T cell recruitment and overall survival in mice with BRCA1- tumors
Doxil therapy significantly prolonged the survival of
animals with BRCA1- tumors
Doxil exposure increased cytotoxic CD8 T cells and
reduced suppressive FoxP3 T cells
Both CD4 and CD8 T cell populations were present in BRCA1- tumors and ascites
Survival measured from the time of tumor inoculation until animals reached 30g due to ascites accumulation
Survival (Days)
P=0.0407
Control
Doxil
Flow cytometry was performed on tumor, ascites, spleen and peripheral blood mononuclear cells (PBMCs). Illustrated are the portion of CD45+/CD3+ T cells present in representative tumor or ascites samples for placebo or Doxil treated mice.
The survival advantage associated with Doxil treatment persisted in the absence of CD4 T cells
An immunodepleting antibody successfully eliminated CD4 T cells from BRCA1- tumors and
ascites
In the absence of CD4 T cells, the proportion of CD8 T cells was
higher in Doxil-treated animals
After treatment with anti-CD4 antibody, a population of CD4-/CD8- cells persisted
Doxil significantly prolonged the survival of CD4-depleted animals
with BRCA1- tumors
Survival measured from the time of tumor inoculation until animals reached 30g due to ascites accumulation
Survival (Days)
** p< 0.05
P=0.0079
Doxil
Control
There was no statistically significant difference in survival after Doxil treatment in the absence of CD8 T cells
An immunodepleting antibody successfully eliminated all CD8 T cells from BRCA1- tumors and
ascites
In mice lacking CD8 T cells, the proportion of mature CD4 T cells,
but not suppressive FoxP3 T cells, was higher after Doxil
treatment
The survival among animals depleted of CD8 cells was not
improved with Doxil treatment
After treatment with anti-CD8 antibody, a population of CD4-/CD8- cells persisted
Survival measured from the time of tumor inoculation until animals reached 30g due to ascites accumulation
* p< 0.05P=0.0952
Doxil
Control
Survival (Days)
*
• Doxil improved survival in a BRCA1- model of ovarian cancer• This effect persisted in the absence of CD4 T cells but is diminished in the absence
of CD8 T cells• Cytotoxic CD8 T cells are necessary for the enhanced response to Doxil observed in
BRCA1- tumor bearing mice• BRCA1- deficient ovarian cancers may be more susceptible to immunotherapeutic
strategies
Limitations: • These results represent a small pilot study and
need to be confirmed in larger cohorts• Unfortunately the national Doxil shortage has
limited our ability to conduct planned experiments
This work was supported by a grant from the
Conclusions
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