The expanding horizon of immunotherapy in the treatment of malignant disorders: Allogeneic hematopoietic stem cell transplantation and beyond

Figures & data

Figure 1. Antigens expressed on tumor cells: targets for immunotherapy. 1) Tumor-associated antigens (TAAs): antigens expressed on tumor cells, while expression on normal cells is minimal or absent. Immune reactivity against TAAs will provoke GVL in the absence of GVHD. Allogeneic as well as autologous immune effectors can be used against TAAs. 2) Hematopoietic tissue-restricted mismatched minor HAs: allogeneic antigens expressed on normal as well as on malignant cells of hematopoietic origin. Immunotherapy against minor HAs can be performed only in the setting of allo-SCT and in cases when donor and recipient are mismatched in the GVH direction. Immune reactivity against minor HAs will provoke GVL in the absence of GVHD. 3) Mismatched HLA, and broadly expressed mismatched minor HAs: allogeneic antigens expressed on malignant cells as well as on normal hematopoietic and epithelial tissues. Immunotherapy can be performed only in the setting of allo-SCT. Immune reactivity will provoke GVL and GVHD. 4) Antigens expressed on malignant cells as well as on normal counterparts, e.g. CD19. Immune reactivity will provoke GVL in the absence of GVHD, but depletion of normal cells expressing the same antigen with all the relevant consequences will occur (e.g. depletion of normal B-cells, hypogammaglobulinemia, infections in case of CD19 targeting). Allogeneic as well as autologous immune effectors can be used.

Table I. Potentially immunogenic tumor-associated antigens.

Type of antigen	Expression on normal cells	Expression on malignant cells	Immunogenicity	Anti-tumor activity	Autoreactivity
Broadly expressed antigens	Yes	Yes	Very low or absent	Low	Yes?^a
Antigens expressed in immune-privileged sites	No	Yes in some cases	Yes	Yes	No
Low-level-expressed antigens	Very low levels	Overexpression in some cases	Yes	Yes	No
Novel antigens	No	Novel proteins encoded by mutated or translocated genes	Yes	Yes	No
Viral antigens	No	Yes in virus-infected malignant cases	Yes	Yes	No

^aAutoreactivity in cases of successful generation of immune reaction.

Figure 2. T-cell and natural killer cell engagers (BiTEs and BiKEs). A: Bispecific T and natural killer cell engagers (BiTEs and BiKEs) consist of two single-chain antibody variable fragments (scFv). In the case of BiTE antibody scFv is specific for CD3 antigen, while in the case of BiKE scFv is specific for CD16. The other scFv is specific for an antigen expressed on the surface of tumor cells, like CD19, CD33, etc. A linker is used in order to combine the two variable regions of the two antibodies. B: BiTE antibodies activate T-cells by binding to their surface CD3 and bring these T-cells in close proximity with the target. In an analogous manner BiKEs activate NK cells by binding to CD16. Activation of effector cell results in perforin and granzyme degranulation and tumor cell apoptosis.