Eradication of medullary multiple myeloma by CD4+ cytotoxic human T lymphocytes directed at a single minor histocompatibility antigen.
OBJECTIVE
The essential role of CD4(+) T cells as helpers of anticancer immunity is indisputable. Little is known, however, about their capacity to serve as effector cells in cancer treatment. Therefore, we explored the efficacy of immunotherapy with sole CD4(+) cytotoxic human T cells directed at a hematopoietic-restricted minor histocompatibility antigen (mHag).


METHODS
In macrophage-depleted Rag2(-/-)γc(-/-) mice, which were also devoid of T, B, and natural killer cells, mHag-specific native T cells or tetanus toxoid (TT)-specific T cells transduced with the mHag-specific T-cell receptor (TCR) were injected to treat full-blown mHag(+) human multiple myeloma tumors.


RESULTS
mHag-specific antitumor responses were achieved after injection of native or mHag-TCR-transduced T cells. Although the therapy completely eradicated the primary tumors in the bone marrow, it failed to control extramedullary relapses, even after repeated T-cell injections. Detailed analyses ruled out mHag or MHC downregulation as mechanisms of extramedullary tumor escape. Impaired T-cell survival in vivo or defective homing to the tumor site were also ruled out as mechanisms behind extramedullary relapses, because injections of TT-loaded antigen presenting cells could facilitate homing of long-term surviving T cells to s.c. tumor sites. Moreover, intratumoral treatment of extramedullary tumors with 3AB11 was also ineffective.


CONCLUSIONS
Taken together, these results for the first time show the feasibility of immunotherapy of primary bone marrow tumors with sole CD4(+) human T cells directed to a tumor-associated mHag. Extramedullary relapses, probably due to microenvironment-dependent inhibitory mechanisms, remain a challenging issue towards effective cellular immunotherapy of hematologic malignancies.
Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, University of Utrecht, Heidelberglaan 100, Utrecht, the Netherlands.
Robbert M
RM
Spaapen
Richard W J
RW
Groen
Kelly
K
van den Oudenalder
Teun
T
Guichelaar
Maureen
M
van Elk
Tineke
T
Aarts-Riemens
Andries C
AC
Bloem
Gert
G
Storm
Anton C
AC
Martens
Henk M
HM
Lokhorst
Tuna
T
Mutis
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D051379:Mice; D015778:Minor Histocompatibility Antigens / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*
D004268:DNA-Binding Proteins; D015778:Minor Histocompatibility Antigens; C499308:Rag2 protein, mouse; D011948:Receptors, Antigen, T-Cell