Immunotherapy may be an effective treatment for HIV-related Kaposi sarcoma (KS), according to the results of a small US study published in Cancer Immunology Research. Two-thirds of people experienced partial or complete remission and the malignancy remained stable in the remaining people. Therapy with an immune checkpoint blockade was also associated with increases in CD4 and CD8 cell counts in most of the people. There was inhibition of a key marker of impaired immune response associated with an increased risk of cancer. Side-effects were generally mild.
The investigators believe that treatment with a checkpoint blockade "may present a promising, novel therapeutic option for HIV-associated Kaposi’s sarcoma with high efficacy and low toxicity.”
KS is an AIDS-defining cancer. It is associated with co-infection with human herpes virus 8 (HHV-8) and can cause lesions on the skin and internal organs. Advanced KS typically emerges in people who are not taking antiretroviral therapy (ART) who have severe immune suppression.
Incidence of KS declined dramatically after the introduction of ART. The immune restoration that accompanies ART can also lead to the stabilisation of existing disease. Despite this, KS remains one of the two most common cancers in people living with HIV, along with non-Hodgkin lymphoma. Some cases persist or develop in people who are taking HIV therapy and who have CD4 cell increases.
The standard treatment for advanced KS is chemotherapy. However, this treatment is often palliative, is associated with significant side-effects and can cause immune suppression. There is therefore a need for new treatments, a therapeutic gap that might be filled by immunotherapy (newer cancer therapies, which help the immune system to attack cancer cells).
Evidence suggests that weakened cellular immunity may have a key role in the development of KS. An association has also been demonstrated between chronic viral infection, cancer, and alterations on programmed death receptor 1 (PD-1) on CD8 cytotoxic-lymphocytes. Impaired CD8 function is associated with HIV-related immune suppression, and HIV-specific CD8 cells can have increased PD-1 expression. Moreover, over-expression of PD lingard 1 (PD-L1) has been observed in several types of tumours associated with viral infections. Previous research suggests that this could be a target for immunotherapy using checkpoint blockade.
Investigators at the Moores Cancer Center at the University of California San Diego therefore report on nine people with HIV-associated KS who received immunotherapy. Eight of these people were treated with nivolumab and one with pembrolizumab. The investigators reported on disease outcomes, changes in tumour pathology, CD4 and CD8 cell alterations and PD-1/PD-L1 status.
The patients received care between August 2013 and December 2017. All were men, their median age was 44 years and the median duration of KS was four years. In four men, KS lesions were restricted to the skin, but the remaining five individuals also had lesions on internal organs or lymph nodes.
All the men were taking ART and seven had an undetectable viral load. Four of the men had a CD4 cell count below 200 cells/mm3, a well-recognised risk factor for KS.
The men had received a median of one previous course of KS therapy (usually chemotherapy).
Immunotherapy was associated with a 67% response rate. One man experienced complete remission, with partial remission observed in five individuals. The remaining three experienced ongoing stable disease for up to 6.5 months of follow-up. There were no cases of disease progression.
CD4 cell count increased in seven men by a median of 104 cells/mm3 and a non-significant increase in CD8 cell count was observed in seven individuals. HHV-8 viral load was undetectable in all the men.
Four men were evaluated for PD-L1 expression in tumours and lymphocytes. Results were negative in all these individuals. Eight men had genetic testing for alterations in tissue and/or blood-derived circulating tumour DNA. Abnormalities in specific genes were recorded in four men.
The treatment had a good safety profile. All drug-related toxicities were mild or moderate. The most frequent side-effects were fatigue in the first four days after therapy, itchy skin, muscle/joint aches, abdominal discomfort and painless separation of finger/toe nails.
The investigators acknowledge that their findings are limited by the small sample size. Larger trials with longer follow-up are needed to give a fuller understanding of the efficacy and safety of immunotherapy for the treatment of HIV-associated KS.
Galanina N et al. Successful treatment of HIV-associated Kaposi sarcoma with immune checkpoint blockade. Cancer Immunology Research, doi:10.1158/2326-6066.CIR-18-0121.