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European Biopharmaceutical Review

Infection Control

According to the US Centers for Disease Control and Prevention (CDC), about 90 per cent of genital warts begin with a sexually transmitted infection by the human papilloma virus (HPV). Transmission of HPV may occur even if the warts are not visible. The virus usually spreads by direct contact with the anus, mouth, penis or vagina of an infected person. Intercourse is not necessary to spread the infection; it can also be transmitted by skin-to-skin contact. In general, genital warts are known to spread relatively easily among partners.

The US National Institute of Allergy and Infectious Diseases reports that as many as two-thirds of those who have had intimate contact with an infected sexual partner could develop warts within about three months of the initial contact. Men and women with a history of anogenital warts have approximately a 30-fold increased risk of developing anal cancer. Indeed, persistent HPV infection in the anal region is thought to be responsible for up to 80 per cent of anal cancers.

Cancer Risk

HPV is now recognised as a significant health problem in the human immunodeficiency virus (HIV) infected population. Although today’s HIV-infected individuals live longer as a result of greatly improved treatments, their immune systems still remain compromised.

Usually, HPV infection can be eliminated by a healthy individual’s immune system within about two years of infection, without treatment. However, certain high-risk HPV strains may cause persistent infection that can lead to local abnormal changes in the infected and surrounding tissues. If left untreated, this can develop into a cancerous lesion, particularly in immunocompromised individuals. Men and women who have HIV are therefore at a higher risk of developing cancer, particularly cancers of the cervix, vulva, vagina, penis and anus. Some head and neck cancers are also associated with HPV infection.

Curbing AIN Progression

Much attention has been focused on diagnosing and following the development of cervical intraepithelial neoplasia (CIN) following HPV infection. Efforts have been made by the scientific and medical community to better understand and treat CIN with the aim of curbing its progression to cervical cancer. With the advent of cervical Pap smear and HPV testing and screening in various regions around the world, the incidence of cervical cancer has declined.

In the same way that persistent HPV infection is understood to be linked to development of CIN – the precursor of cervical cancer – persistent HPV infection has also been implicated in the development of anal intraepithelial neoplasia (AIN) – the precursor to anal cancer.

There are marked similarities in the biological and pathological profiles of cervical cancer and anal cancer, which suggests that the incidence of anal cancer may be reduced by developing strategies which can restrict the progression of AIN to cancer.

Prevalence Estimates

There is a scarcity of literature with which to try to accurately estimate the prevalence of HPV in HIV-infected individuals and, by extension, the prevalence of high-grade AIN in both men and women who are HIV/HPV co-infected in the US. The CDC puts the number of HIV-infected adults in the country at about 1,148,200. To try to estimate the range of individuals with high-grade AIN in the HIV/HPVinfected adult population in the US, the following methodology was employed:
  • The target patient population began with the total number of HIV-infected men and women in the US
  • Next, the HIV-infected population was split into three groups: men who have sex with men (MSM); women; and all others
  • Each group was then broken down into the percentage that are co-infected with HPV
  • Finally, each group that was determined to be co-infected was broken down into the percentage who were diagnosed with AIN

Of the total HIV-infected population, about 597,064 are MSM and about 287,050 are women. Some 23 per cent, or 264,086, represent all others. Taking into consideration the variable estimations of different infected populations, and using the methodology above, this leads to a calculated range of between 94,594 and 372,086 individuals (both men and women) in the US who are likely to have high-grade AIN in the co-infected HIV/HPV population.

HIV treatment has now progressed to the point that it could be considered a manageable disease in most patients (that is, patients can live with the disease for a long period of time, with relatively good quality of life). As a result, HPV infection is surfacing as a rapidly growing problem in the HIVinfected population. The prevalence of AIN can only be estimated from surveying the available scientific literature as there is seemingly no comprehensive source(s) of information for estimating the prevalence of HIV/HPV co-infected individuals. The incidence of anal warts in HIV/HPV co-infected patients is likely to be larger than the estimated incidence of high-grade AIN, but there is insufficient literature to accurately document this estimate.

Enter Immunotherapy

The Naval Medical Center in San Diego – a referral centre of excellence for HIV/AIDS care of active duty, family members and retired individuals since the start of the HIV epidemic in the 1980s – is investigating the use of an immunotherapy against anal warts in HIV/HPV co-infected individuals. The research specifically involves the use of leukocyte interleukin injection (LI) (Multikine®), an investigational new drug product produced by CEL-SCI Corporation. A cooperative R&D agreement between the US Naval Medical Center and CEL-SCI will enable a Human Subjects Institutional Review Board approved Phase 1 dose escalation study of Multikine in HIV/HPV co-infected men and women with peri-anal warts.

Multikine is currently being investigated in a global Phase 3 trial as a neoadjuvant/adjuvant treatment of treatment-naïve cancer patients with locally advanced squamous cell carcinoma of the head and neck. In addition, Phase 1 clinical trials have been performed with Multikine in male and female HIV-infected subject volunteers, and in women volunteers with cervical dysplasia who were infected with both HIV and HPV. The latter results suggest that the Multikine treatment regimen might be useful in clearing HPV and HPV-infected tissue and lesions of the cervix which, if not treated, could lead to cancer of the cervix.

Multikine Therapy

Multikine (LI) is a complex biologic product that contains a mixture of naturally derived and naturally occurring human pro-inflammatory cytokines (including IL-2, IL-1β, GM-CSF, TNFα and IFNγ, and other small biological molecules) with immunomodulatory activity. Each cytokine in this mixture has a distinct effect on the host and tumour, and the sum of all these is thought to affect solid tumour destruction in cancer patients. The pro-inflammatory cytokines in Multikine also have the potential to activate an array of immune-mediated anti-infective responses in treated individuals, which are thought to be required to be able to clear infections.

The therapy is administered locally, percutaneously (peritumorally and perilymphatically to cancer patients), and aims to elicit a maximal immune response. In the studies of perianal warts that are currently being considered, Multikine would be injected perilesionally at the base of the anal wart.

It is hoped that a strong, local specific immune response would develop, which would result in the elimination of the anal wart and impact the underlying cause of disease – the HPV persistent viral infection – while at the same time having an impact on the AIN status of the subject volunteers.

The purported mechanism of action of Multikine has been published in the Journal of Clinical Oncology. It describes how the local/regional injection percutaneously (peritumorally and perilymphatically injected) of mixed interleukins overcomes local immunesuppression; and is thought to break tumour tolerance to tumour antigens, change tumour cellular immune infiltrate, and affect the tumour microenvironment – allowing for an effective and sustainable local antitumour immune response.

Killing HPV-Infected Cells

The pro-inflammatory cytokines in Multikine, such as TNFα, may also be able to activate transcriptional factors – for example, NF-kB. A critical downstream target of NF-kB gene encoding for IL-6 (a cytokine also known to be present in Multikine) is to stimulate an array of anti-infection processes, including the synthesis of acute phase protein, proliferation of B cells, neutrophil production and differentiation of Th17 helper T cells, all of which are thought to be necessary in bringing about an anti-infective response.

In addition, IFNγ (also present in Multikine) may result in specific antiviral activity, including anti-HPV activity where studies conducted by others with the administration of purified or recombinant IFNγ directly to, or in the vicinity of, HPV warts have shown lesion regression accompanied by activation of T cell mediated immune response, with influx of activated T lymphocytes. This same/similar clinical and histological manifestation has been shown previously, with the administration of Multikine in the HIV/HPV CIN population.

Specific Needs

The goal of HIV care is empowering people to live long and productive lives with the virus. When it comes to the risk of developing HPV-related cancers, HIV-positive individuals need expanded arsenals that will be able to address their specific needs – and clinical trials, such as those outlined here, will hopefully provide answers for those needs.

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Eyal Talor is Chief Scientific Officer of CEL-SCI. He is a clinical immunologist with over 19 years of hands-on management of clinical research and drug development for immunotherapy applications. Eyal’s expertise includes biopharma product development, Good Manufacturing Practices and quality control testing. He has previously worked at CBL and SRA Technologies. Eyal received his PhD in Microbiology and Immunology from the University of Ottawa, Canada, and had postdoctoral training in clinical and cellular immunology at Johns Hopkins University.
Eyal Talor
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