Immuno-oncologic Approaches: CAR-T Cells and Checkpoint Inhibitors

Abstract

Advances in understanding myeloma biology have shown that disease progression is not only the consequence of intrinsic tumor changes but also of interactions between the tumor and the microenvironment in which the cancer grows. The immune system is an important component of the tumor microenvironment in myeloma, and acting on the immune system is an appealing new treatment strategy. There are 2 ways to act toward immune cells and boost antitumor immunity: (1) to increase antitumor activity (acting on T and NK cytotoxic cells), and (2) to reduce immunosuppression (acting on myeloid-derived stem cells and T regulatory cells). Checkpoint inhibitors and adoptive cell therapy (ACT) are 2 of the main actors, together with monoclonal antibodies and immunomodulatory agents, in the immune-oncologic approach. The aim of checkpoint inhibitors is to release the brakes that block the action of the immune system against the tumor. Anti-programmed death-1 (PD-1) and PD-1-Ligand, as well as anti-CTLA4 and KIR are currently under evaluation, as single agents or in combination, with the best results achieved so far with combination of anti-PD-1 and immunomodulatory agents. The aim of ACT is to create an immune effector specific against the tumor. Preliminary results on chimeric antigen receptor (CAR) T cells, first against CD19, and more recently against B-cell maturation antigen, have shown to induce durable responses in heavily pretreated patients. This review focuses on the most recent clinical results available on the use of checkpoint inhibitors and CAR-T cells in myeloma, in the context of the new immune-oncologic approach.

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

“…Novel cell therapies and several potential targets for CAR T cells are under investigation in MM (45,46) (Table 2). Anti-CD38 and anti-SLAMF7 CAR T cells showed anti-MM effects in preclinical models (47,48), but the expression of both target antigens on other normal tissues including hematopoietic lineages and immune effector cells may cause off-tumor toxic effects limiting their long-term clinical use.…”

The future of immune checkpoint blockade immunotherapy: towards personalized therapy or towards combination therapy

“…This strategy will not only provide systemic immunity that is required for effective cancer immunotherapy (14), but may also increase local infiltration of T and NK cells in tumor microenvironment. In line with this idea, a recent review summarized the most recent clinical results on the use of checkpoint inhibitors and CAR-T cells in multiple myeloma (15). As such, multiple myeloma could be an appropriate candidate to test the idea of the combination therapy of checkpoint blockades with CAR-T therapy to increase infiltration of T cells in tumor microenvironment to overcome the resistance and thus to optimize the efficacy of immune checkpoint blockade therapy.…”

Monoclonal Antibodies and Multiple Myeloma: All in All It's Just Another Brick in the Wall?

“…Despite the revolutionary therapeutic success in some solid malignancies and in Hodgkin's lymphoma, the role of check‐point inhibitors in MM remains controversial . Monotherapy with nivolumab had no relevant activity in RRMM .…”

“…Notably, the rate of autoimmune disorders was significant in one study . Thus, several trials were initiated to evaluate various combinations of check‐point inhibitors with other agents (in particular IMIDs and MoAbs) . On July 3, 2017, however, the FDA placed a clinical hold on two phase III trials with pembrolizumab (KEYNOTE‐183 and KEYNOTE‐185) enrolling patients with RRMM and ordered the discontinuation of the lenalidomide/dexamethasone/pembrolizumab arm of another trial (KEYNOTE‐023), because interim results showed that pembrolizumab was associated with an unexplained increased risk for death.…”

“…Finally, MoAbs should soon be integrated and positioned within the context of an emerging scenario in which, along with “novel‐novel agents,” adoptive immunotherapy with chimeric antigen receptor T cells targeting B‐cell antigens and newer examples of precision medicine (i.e., the Bcl‐2 inhibitor venetoclax in MM patients carrying t(4;11) or the first‐in‐class selective inhibitor of nuclear export compound Selixenor ) could play a relevant therapeutic role for MM patients in the near future.…”