Immunological Aspects of Richter Syndrome: From Immune Dysfunction to Immunotherapy

Simple Summary Richter Syndrome is the development of an aggressive lymphoma in patients affected by chronic lymphocytic leukemia, the most common leukemia in adults. This transformation occurs in 1-10% of chronic lymphocytic leukemia patients and represents an unmet clinical need due to its refractory behavior towards conventional therapies. Recently, the pathogenesis of Richter Syndrome has been shown to be partly related to dysfunction of the immune system, and several immune alterations have been found in patients affected by this disease. Hence, the lack of effective therapies may be overcome through immunotherapy, a type of treatment that improves the immune system response against cancer cells. Several immunotherapeutic approaches have been developed and are currently under investigation, including the use of naked monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, and chimeric antigen receptor-T cells. Richter Syndrome (RS) is defined as the development of an aggressive lymphoma in patients with a previous or simultaneous diagnosis of chronic lymphocytic leukemia (CLL). Two pathological variants of RS are recognized: diffuse large B-cell lymphoma (DLBCL)-type and Hodgkin lymphoma (HL)-type RS. Different molecular mechanisms may explain the pathogenesis of DLBCL-type RS, including genetic lesions, modifications of immune regulators, and B cell receptor (BCR) pathway hyperactivation. Limited data are available for HL-type RS, and its development has been reported to be similar to de novo HL. In this review, we focus on the immune-related pathogenesis and immune system dysfunction of RS, which are linked to BCR over-reactivity, altered function of the immune system due to the underlying CLL, and specific features of the RS tumor microenvironment. The standard of care of this disease consists in chemoimmunotherapy, eventually followed by stem cell transplantation, but limited possibilities are offered to chemo-resistant patients, who represent the majority of RS cases. In order to address this unmet clinical need, several immunotherapeutic approaches have been developed, namely T cell engagement obtained with bispecific antibodies, PD-1/PD-L1 immune checkpoint blockade by the use of monoclonal antibodies, selective drug delivery with antibody-drug conjugates, and targeting malignant cells with anti-CD19 chimeric antigen receptor-T cells.