Gleevec may improve immune functioning

[Guest guest]

As many of you know, there are hints in the literature that IM (Gleevec)

interferes with certain aspects of the immune system. If true, this presents

us with a couple of problems: first, it's unfortunate for us if by

suppressing the tumor fighting capabilities of our immune system IM were to

allow other cancers to gain a foothold while keeping our CML at bay (it was

this concern, and others, which led me to try cycling on and off IM for the

past couple of years - a practice which I've suspended in light of recent

positive qPCR's). Second, despite all the great new drugs in the pipeline,

the most promising strategies for curing CML are probably those that enhance

our own (or a donor's, in the case of a mini-SCT) immune system's response

to the disease, so we can recognize and kill residual cells that are

insensitive to drugs. If IM inhibited the mechanisms whereby vaccination

induces immunity, these otherwise promising strategies would be compromised.

Happily, this February's " Blood " Journal contains an article, abstracted

below, indicating that IM may actually improve immune functioning in certain

important respects: " In spite of the valid concerns raised by those studies

demonstrating that imatinib mesylate can impair DC maturation and T-cell

function, our in vivo results together with those from Zeng et al indicate

that treatment of a tumor-bearing host with STI-571 certainly did not impair

antitumor immune responses but instead resulted in enhancement of T-cell

responses to vaccination strategies. "

The authors bolster their case with findings from other studies: " Further

evidence supporting the potential positive immunomodulatory effects of

imatinib mesylate has been provided in a murine model of bcr-abl+ murine

leukemia and in two recently completed clinical trials for patients with CML

in which vaccination strategies were added to imatinib mesylate. First, Zeng

et al have shown that the combination of this drug with chaperone-rich cell

lysate­loaded DCs resulted in activation of antigen-specific T cells and

potent antitumor activity against bcr-abl+ leukemic cells. In the clinical

arena, Bocchia et al have found that in CML patients with persistent disease

despite treatment with STI-571, vaccination with a P-210­derived

multipeptide vaccine (CMLVAX100) induces cytogenetic and even molecular

improvements in the majority of treated patients. Furthermore, in this

cohort of patients, prolonged treatment with STI-571 does not adversely

affect T-cell responses since peptide-specific proliferation and IFN-gamma

production by CD4+ T cells were clearly detected following multiple

immunizations with CMLVAX100. In a second study, Li et al treated imatinib

mesylate­resistant CML patients with a combination of this drug and an

autologous vaccine consisting of heat-shock protein (HSP) obtained from the

patient's own malignant cells. This strategy also resulted in improved

cytogenetic and molecular responses as well as in the expansion of

IFN-gamma­producing CD8+ T cells directed specifically against autologous

tumor cells. "

As members of this list can attest, there is reason for skepticism regarding

the reported findings and conclusions of the heat-shock protein study;

nevertheless, the overall thrust of this article is a hopeful one.

There are other interesting (though complicated) findings in this article,

including the fact that in a mouse CML model, " treatment with [imatinib] was

able to convert a T-cell encounter with antigen/APC from a tolerizing event

into an activating event " . I will post a PDF of it temporarily in the Files

section of the webpage.

Cheers,

R

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Abstract:

Imatinib mesylate (STI-571) enhances antigen-presenting cell function and

overcomes tumor-induced CD4+ T-cell tolerance

Hongwei Wang, Fengdong Cheng, Cuenca, Pedro Horna, Zheng Zheng, Kapil

Bhalla, and M. Sotomayor

From the Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer

Center & Research Institute at the University of South Florida, Tampa, FL.

Tumor antigen­specific T-cell tolerance imposes a significant barrier to the

development of effective therapeutic cancer vaccines. Bone marrow­derived

antigen-presenting cells (APCs) are critical in the induction of this

unresponsive state. Here we show that in vitro treatment of APCs with the

tyrosine kinase inhibitor, imatinib mesylate (STI-571), enhances the

activation of naive antigen-specific T cells and restores the responsiveness

of tolerant T cells from tumor-bearing hosts. Furthermore, in vivo treatment

with STI-571 not only prevented the induction of tolerance in tumor-specific

CD4+ T cells, preserving their responsiveness to a subsequent immunization,

but also resulted in enhanced vaccine efficacy. These findings demonstrate

that tolerance to tumor antigens is not an insurmountable obstacle and

points to modulation of APC function as a promising strategy in the

immunotherapy of cancer.