Over the past decade, immune therapy has transformed the therapeutic landscape in cancer, and is now well established as a major pillar of cancer therapeutics, alongside surgery, radiation or chemotherapy. Two broad areas, specifically, blockade of inhibitory immune checkpoints and T-cell redirection with chimeric-antigen receptor-T cells or bispecific antibodies, have led to impressive tumor regression. However, the application and understanding of these exciting immune therapies in cancer populations have not been uniform, leading to several groups such as older adults being understudied. The impact of race, ethnicity and social determinants of health on access as well as response to these exciting therapies are also not clearly understood.

Cancer is primarily a disease of old age; more than half of all new cancer diagnoses in the Western world are now made above the age of 65. As society ages, the percentage of older patients with cancer will continue to rise. Unfortunately, international cancer registries show that for almost all types of cancer, disease-specific survival deteriorates with increasing age. Many studies also show that older patients as a group have often hardly benefited from recent treatment developments. This should come as no surprise as the often intensive and toxic nature of many new treatments requires an overall robust health status from those being treated. Comorbidities and frailty are often contraindications to intensive therapies and place patients at risk of side effects and poor outcomes. The very heterogeneous health status of aged people is therefore considered one of the important causes of outcome disparities between older and younger patients with cancer.

Immunotherapy with immune checkpoint inhibitors (ICIs) now seems a remarkable game changer. Due to selection bias, a common problem in oncology studies, randomized clinical trials of immunotherapy hardly yield robust information on treatment outcomes of older patients with an average health status or very old patients. However, several observational studies have now confirmed that efficacy is preserved and adverse events of immunotherapy are not or hardly increased in older patients. The fact that immunotherapy can be an ‘old age-inclusive’ therapeutic development is encouraging, but also raises many questions that require urgent research.

The proposed mechanism of action of ICIs is blocking the interaction between the inhibitory T-cell checkpoints and their ligands on myeloid cells and tumor cells, resulting in the activation of the T-cell response. Yet T cells are also among the immune cells that undergo dysfunction with aging. Regarding other immunotherapies than ICIs like T-cell redirection, there are similar questions raised about the impact of aging phenotypes that need urgent investigation.

As with aging, functional aspects of the immune system may also be impacted by race, ethnicity and social determinants of health. Therefore it stands to reason that these variables, though understudied, will also impact the biology, efficacy, tolerance to these therapies. Racial/ethnic factors and social determinants of health also impact access to these therapies as well as clinical trials.

As significant gaps still exist in cancer immunotherapy research, both at the clinical and biological levels in understudied populations (older patients with cancer or those from racial/ethnic minorities) JITC will publish a series of reviews on this topic in the coming months. Authors from diverse backgrounds were invited to review existing research on aging and different types of immunotherapy for solid cancers and hemato-oncology.

With this series, we aim to inspire researchers who can fill knowledge gaps in immunotherapy regarding the role of aging, race, ethnicity and social determinants of health.

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