IT by CD40 stimulation and IL2 against renal cell carcin

Project: Research project

Description

DESCRIPTION (provided by applicant): CD40/CD40 ligand interactions have been
demonstrated to be critical co-stimulatory molecules in the generation of a
successful immune response. We hypothesized that it may be possible to augment
the immunostimulatory effects of CD40 stimulation by combining it with cytokine
therapy. IL2 has been demonstrated to augment both adaptive and innate immune
responses. Thus far, cytokine therapy has concentrated on using combinations of
cytokines. We reasoned that the use of CD40 stimulation to promote dendritic
cell development and function coupled with the properties of IL2 to promote T
cell function would result in synergistic anti-tumor effects in vivo. Using a
highly metastatic murine renal cancer model we found that strong synergistic
anti-tumor effects resulted if CD40 stimulation was applied with IL2 therapy
whereas no effect was observed using either agent alone. We now propose to
delineate the mechanism underlying these anti-tumor effects and optimize the
immunotherapeutic potential of this regimen. Toward this goal we have developed
5 specific aims: Specific Aim 1 will assess the effects of CD40 stimulation
using agonist antibodies to CD40 in combination with IL2 on various metastatic
renal tumor models (using both CD40+ and CD40- tumor lines) to determine the
extent at which this approach is efficacious and to determine if specific
immunity results upon rechallenge. Specific Aim 2 will explore the
immunomodulatory effects of this regimen through the assessment of various
components of both the innate (dendritic, NK) and adaptive (T and B) immune
system as well as the role of cytokines. Specific Aim 3 will determine the role
of CD40 on various tissues in response to this regimen through the use of CD40
-/- mice and various chimeras constructed by them. Specific Aim 4 will
ascertain the efficacy of a recombinant soluble ligand for CD40 (srCD40L) to
determine if similar immunomodulatory and anti-tumor effects can be obtained
with this combination with IL2, particularly in light of recent data
demonstrating extreme toxicities associated with antibodies to CD40 given after
cytoreductive conditioning. Specific Aim 5 will then examine the effects of
CD40 stimulation and IL2 in models in which cytoreductive conditioning is
applied to advanced tumor-bearing mice. Both potential toxicities (which will
be sought to be overcome), effects on immune reconstitution, and anti-tumor
effects will be evaluated. This last model will most closely resemble advanced
tumor bearing patients undergoing a debulking procedure followed with
immunotherapy to remove the minimal residual disease. This proposal examining
induction of costimulation with CD40 followed with IL2, should yield
significant insights, not only to the efficacy of this combination approach in
cancer, but also as an immunostimulatory regimen for infectious disease.
StatusFinished
Effective start/end date9/1/021/31/18

Funding

  • National Institutes of Health: $278,832.00
  • National Institutes of Health: $302,123.00
  • National Institutes of Health: $290,363.00
  • National Institutes of Health: $290,363.00
  • National Institutes of Health: $57,833.00
  • National Institutes of Health: $289,821.00
  • National Institutes of Health: $287,574.00
  • National Institutes of Health: $290,363.00
  • National Institutes of Health: $39,322.00
  • National Institutes of Health: $302,123.00
  • National Institutes of Health: $322,422.00
  • National Institutes of Health: $59,621.00
  • National Institutes of Health: $293,059.00
  • National Institutes of Health: $287,574.00
  • National Institutes of Health: $296,163.00

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Interleukin-2
Immunotherapy
Neoplasms
Adipose Tissue
Kidney
Cytokines
Caloric Restriction
CD40 Ligand
T-Lymphocytes
Macrophages
Immunosuppressive Agents
Cancer Vaccines
Cell Death
Renal Cell Carcinoma
Cytokine Receptors
Ghrelin
Antibodies
Therapeutics
Body Composition

ASJC

  • Medicine(all)