Cancer immunotherapy in special challenging populations: recommendations of the Advisory Committee of Spanish Melanoma Group (GEM)



# Supplementary appendix
This appendix has been provided by the authors to give readers additional information about their work.

## References.....................................................................................................................................11
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## Supplementary data: incidence and pathophysiology

## Hiv-1 infection
HIV-1 virus produces a rapid depletion of CD4 + T cells, both due to a direct cytopathic effect on infected CD4 + T cells, as well as an immune mediated effect on uninfected bystander 1 CD4+ T cells, while CD8+ T cell counts increase due to an expansion of oligoclonal CD8 + T cells, leading to a low ratio of CD4 + /CD8 + T cell counts. When patients are treated with antiretroviral drugs (ART), CD4 + T cell counts usually increase and are recovered, but in some cases, mainly if ART is initiated late in the course of the infection, CD4 + T cell counts could remain low. Moreover, patients who recover CD4 + T cell counts, can also retain high CD8 + T cell counts, leading to a low CD4 + /CD8 + ratio with normal CD4 + T cell counts. [bib_ref] Immunotherapy in People With HIV and Cancer, Puronen [/bib_ref] The normal CD4 + /CD8 + ratio in healthy persons is not fully defined, but usually it is above 1.5. [bib_ref] Imbalance in the game of T cells: What can the CD4/CD8 Tcell..., Mcbride [/bib_ref] In persons infected by HIV-1 a low CD4 + /CD8 + ratio correlates with a stage of immune disfunction and chronic inflammation with a higher risk of mortality. [bib_ref] CD4:CD8 ratio as a frontier marker for clinical outcome, immune dysfunction and..., Lu [/bib_ref] In the prospective study conducted by Uldrick et al, inclusion of patients with less than 200 CD4 + T cells/mm 3 was allowed when they had a CD4 + /CD8 + ratio above 0.4. 5

## Viral hepatitis
Around 30% and 95% of adults infected by HCV or HBV, respectively, will spontaneously clear the virus. Despite multiple HBV plasma markers, the most important are hepatitis B surface antigen (HBsAg), which is the marker of chronic hepatitis B infection, and the antibody against hepatitis core protein (anti-HBc), which is the marker of previous exposition

## Tuberculosis infection
Most TB cases are caused by Mycobacterium tuberculosis (MT). The bacillus is carried in airborne particles, called droplet nuclei, of 1-5 microns in diameter and they are generated when persons who have pulmonary or laryngeal TB disease cough, sneeze, shout, or sing.When the tubercle bacilli reach the alveoli of the lungs, they are ingested by alveolar macrophages that form a barrier shell, called granuloma. Although most of these bacilli are destroyed or inhibited, a small number of them can multiply intracellularly, and they are released when the macrophage cell dies. These bacilli may spread through the lymphatic channels or the blood stream to more distant tissues and organs (regional lymph nodes, apex of the lung, kidneys, brain, and bones).In summary, there are three clinical situations: infection eliminated, latent TB infection (LTBI) and subclinical or active TB disease. People with LTBI cannot spread the infection to other persons. Within weeks after infection, the immune system is usually able to stop the multiplication of the bacilli, preventing further progression.Conversely, persons with TB disease are usually infectious and may spread the bacteria to others. It is caused because the tubercle bacilli overcome the immune system and multiply.Without treatment, approximately 10% of persons with a normal immune system infected by MT will develop TB disease (5% in the first or second year, and 5% later in life). Some people are at higher risk than others to develop TB disease, for example persons with non-treated HIV infection and people who are receiving immunosuppressive therapy.People with LTBI do not have any symptoms. When TB bacilli grow in the lungs, it causes symptoms, such as: cough that lasts 3 weeks or longer, pain in the chest and coughing up blood or sputum. Other symptoms of TB disease may include: weakness or fatigue, weight loss, no appetite, chills, fever and night sweats. In 15-20% of cases, TB affects other organs, so they have additional symptoms and complications, including, meningitis, ascites, Pott's disease (TB spondylitis), scrofula (lymphadenitis) and genitourinary alterations.Mantoux tuberculin skin test (TST) is performed by intradermal injection of tuberculin purified protein into the inner surface of the forearm. Usually, the injection should produce a pale elevation of the skin (a wheal) 6 to 10 mm in diameter. The skin test reaction should be read between 48 and 72 hours after administration. The reaction should be measured in millimeters of the induration, but not measuring the erythema. The diameter of the indurated area should be measured across the forearm (perpendicular to the long axis). BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)
[table] Table S1: Summary of the main studies and reviews [/table]
[table] Table S2: Simplified interpretation of the serological status for Hepatitis B. * Usually low HBV DNA values (< 200 IU/mL).Footnote: For the diagnosis of chronic HBV infection, several determinations in plasma or serum are used: hepatitis B surface antigen (HBs Ag), hepatitis B e antigen (HBe Ag), antibody against HBs Ag (anti-HBs), antibody against hepatitis core protein (anti-HBc) and the determination of HBV DNA by PCR. The presence of HBV DNA in serum or plasma is the gold standard for the diagnosis of the infection, as it denotes active infection and correlates with the infectivity of the patient. Nevertheless, for screening of a HBV infection, serological tests are initially indicated, and determination of viral DNA is reserved for doubtful cases. Chronic HBV infection is defined by the presence of HBs Ag in the blood for longer than six months. If negative, chronic HBV infection is typically ruled out. As Anti-HBs is a neutralizing antibody that confers protective immunity, it can be positive in previous vaccinated patients without infection and also in persons that have overcome the infection. The difference between both situations is that only persons that have been infected have detectable anti-HBc antibodies. It is very infrequent, but possible, that persons with detectable anti-HBs antibodies and HBs Ag positive are chronic carriers. The presence of HBe Ag indicates active viral replication and it does not discriminate between acute or chronic hepatitis. The presence of Anti-HBc indicates a prior exposure to the virus, but it is not a neutralizing BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) antibody and it does not discriminate between acute or chronic infection. In some cases, anti-HBc antibody Ig G can be the only positive marker of infection, as in the window period of acute infection, but also in some cases with chronic infection. This peculiar serological profile occurs in 1% in low-prevalence countries, but close to 20% of blood donors in countries with endemic infection. The presence of an isolated IgG anti-HBc may suggest an occult HBV infection. Occult HBV infection is currently defined as the absence of circulating HBsAg in individuals positive for HBV DNA. Usually, if anti-HBc is negative, a chronic infection can be ruled out, but in immunocompromised chronically infected patients it can be negative, although viral DNA is positive. More than 20% of the occult carriers are negative for all serum markers of HBV infection and they are called "seronegatives". [/table]