Immune Conditioning in Premalignant HPV Disease

Cornelia Trimble, M.D.

Johns Hopkins University

Funded in June, 2007: $255000 for 3 years
LAY SUMMARY . ABSTRACT .

LAY SUMMARY

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Identifying Immune Responses to the Virus that Causes Cervical Cancer May Lead to Therapeutic Vaccine

Researchers will explore why immune responses in some women enable progression of the virus that eventually causes cervical cancer, while immune responses in other women effectively clear the virus. They also will assess whether immunotherapy in women with the pre-cancerous condition strengthens their immune responses.  

Sexually transmitted human papillomavirus (HPV) causes cervical cancer.  It remains the second leading cause of cancer death in women worldwide, even though HPV infection regresses spontaneously in about a quarter of infected women, can be identified through screening, and can be effectively treated in early stages of the cancer. A newly available vaccine prevents cervical cancer, but must be administered to pre-adolescent girls before they become sexually active. Substantial parental resistance to vaccinating their young daughters in this country and logistical barriers in developing countries portend the continued need to develop effective immunotherapies.    

Research has shown that the immune system recognizes HPV infection.  This investigator’s work has shown that in approximately 25 percent of women the immune system actually rejects or heals HPV disease after it has begun.  The researchers hypothesize that in the 75 percent who do not "self-heal," the recognition of the virus by immune T cells, or their attacks against it, are inhibited by factors associated with the HPV virus, at the site of the pre-cancerous lesions. They will measure and compare the strength and quality of immune T cell responses in a cohort of women identified to have HPV infection, some of whom will clear the virus while others will not. They also will see whether the magnitude and quality of T cell responses is strengthened in 48 women with the pre-cancerous condition who are participating in a clinical trial, funded by others, of a therapeutic vaccine.  

Significance: Understanding immune factors associated with successful remission of the HPV virus, or its unobstructed progression to a pre-cancerous stage, is expected to improve the design of therapeutic vaccines to treat this deadly disease.

ABSTRACT

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Immune Conditioning in Premalignant HPV Neoplasia

HPV-associated neoplasia of the cervix presents a compelling opportunity to test antigen-specific immunotherapies because expression of two nonself, viral antigens, E6 and E7, are together functionally required to initiate and maintain high grade dysplastic lesions (CIN2/3), the lesion which is the immediate precursor to invasive cervical cancer.  Expression of these proteins is functionally required to maintain the transformed phenotype. 

Globally, HPV type 16 alone accounts for over half of all cervical malignancies.  Weak but reproducibly measurable endogenous HPV-specific T cell responses in peripheral circulating lymphocytes (PBLs) obtained from CIN2/3 patients suggest that viral antigens are presented to and recognized by the immune system. In fact, between 20-25% of established CIN2/3 lesions regress completely over a 15-week prospective study window. However, the fact that neither the vigor nor the breadth of endogenous responses to HPV16 antigens measured in the peripheral blood appears to correlate consistently with lesion regression implies either that HPV16 E7-specific effector cells do not consistently access lesions, or that they do, and are dysfunctional in the lesion milieu.

The overall goal of this work is to determine whether we can measure molecular evidence of common mechanisms of immune suppression in CIN2/3 lesions. Two likely mechanisms of immunologic failure in the clinical setting of persistent viral infection of the lower genital tract mucosa include (1) expression of inhibitory ligands, both by lesional epithelial cells and by polarized antigen presenting cells (APCs) associated with lesions, and (2) recruitment and expansion of regulatory T cells (Treg) as a function of self-limiting immunologic homeostasis. 

The overall hypothesis for this proposal is that lesion-mediated immune conditioning plays a central role in shaping the host immune response very early in cervical disease, well before invasion.   We will determine whether the local immune microenvironment correlates with either the quality or the magnitude of endogenous immune response to HPV antigens.  As a corollary, we will determine whether the quality of endogenous, baseline response to HPV antigens correlates with subsequent response to therapeutic vaccination.  Finally, we will determine whether direct manipulation of the immunologic milieu to change an essentially tolerogenic setting enhances effector activity of vaccine-induced response.