Exhausted and outnumbered: CD4+ T cells in the myeloma battlefield

The role of the immune system in the pathogenesis of hematologic malignancies has long been the subject of research studies (1). More recently, knowledge on the mechanisms by which immune cell subsets contribute to immune tolerance and help blood cancers gain control of the microenvironment has made considerable progress (2). Indeed, the discovery and role of checkpoint inhibitors as well as the ability to successfully manipulate effector immune cells has led to a revolution in cancer treatment (3). To our knowledge, seven immune checkpoint inhibitors are currently approved for treatment of at least fifteen different tumor types, including lymphoma (4). Tisagenlecleucel and axicabtagene, both CD19 targeted chimeric antigen receptor T cell product (CAR T) with different costimulatory domains were the first of such therapies to be approved for treatment of leukemia (tisagenlecleucel) and later non-Hodgkin’s lymphoma (both tisagenlecleucel and axicabtagene) by regulatory agencies (5–7). In the field of multiple myeloma, it is increasingly being recognized that dysregulation of the quantity and composition of immune cell subsets in the tumor microenvironment leads to progression from monoclonal gammopathy of unknown significance (MGUS) to overt myeloma (8). Immune dysregulation has also been linked to a higher risk of “graft versus host”-like syndrome after autologous stem cell transplantation (ASCT) and poor clinical outcomes in newly diagnosed myeloma (9–11).

In this issue of Leukemia and Lymphoma, Gu and colleagues evaluate the role of T lymphocyte subsets in the peripheral blood of one hundred and ten newly diagnosed myeloma patients (12). The study period (2012–2016) belongs to the era of novel agents with patients treated with bortezomib and immunomodulatory agents, however only a small subset of patients underwent ASCT (14%). The authors measured levels of CD3+CD4+ and CD3+CD8+ T cell subsets in peripheral blood at baseline for these patients. They found that the median CD3+CD4+ T cell count was low at 0.41 × 10⁹/L. Patients who had higher CD3+CD4+ T cells (>0.5 × 10⁹/L) had longer progression free survival (PFS) and overall survival (OS) compared to those who didn’t (PFS 66 vs 34 months and OS 31.5 vs 18.5 months). A higher CD4+/CD8+ T cell ratio (>0.7 × 10⁹/L) was associated with longer PFS (24 vs 10 months) and OS (24 vs 10 months) in this cohort of patients. No relationship was seen between CD3+CD8+ T cells counts in peripheral blood and clinical outcomes. Overall, lower CD3+CD4+ T cell counts were associated with lower hemoglobin (hazard ratio (HR) 2.3) and higher LDH (HR 2.4), Beta-2-microglobulin (HR 2.7) and high-risk cytogenetics (HR 2.7).

Although similar findings had been reported elsewhere, the results of this study are important as they confirm that the composition of the immune system at baseline remains an important predictor of clinical outcomes in the era of novel agents in myeloma patients (1). The development of CD38 monoclonal antibodies daratumumab and isatuximab is one of the major recent advances in the treatment of myeloma. Studies investigating their use added to the standard of care in frontline myeloma are ongoing (IMROZ- NCT03319667 transplant ineligible patients and PERSEUS – NCT03710603 transplant eligible patients) or have been recently reported (GRIFFIN – transplant eligible patients) (13). It remains to be seen whether immune cell composition remains an independent predictor of clinical outcome in patients treated with quadruplet therapies. Immune dysregulation occurs early in myeloma pathogenesis and considerable research effort is in place to develop immunotherapy treatment strategies for early myeloma (14). For example, PD-L1 on myeloma cells has been associated with an increased risk of progression from smoldering to multiple myeloma (15). A pilot study of single agent pembrolizumab in 13 patients with smoldering myeloma led to an extraordinary responder who remains in complete remission minimal residual disease negative after only three doses of pembrolizumab 3 years post therapy. Extensive correlative analysis showed that this patient had a pre-existing immune response which was augmented by pembrolizumab, whereas the non-responders had features of T-cell exhaustion and may require combination immune therapy to restore checkpoint function (16). Strategies that enhance antitumor T-cell responses need to be further explored in early myeloma.

A biologics license application for idecabtagene vicleucel (bb2121), a BCMA targeted CAR T cell product, has been filed with the US Food and Drug Administration for approval in the treatment of relapsed myeloma (17). Given high responses in this patient population, trials are ongoing to investigate the role of cell therapy in high-risk newly diagnosed myeloma for whom standard options may not result in tumor remission (KarMMa-4; NCT04196491). In fact, the possibility exists that cell therapy in earlier lines will result in deeper and longer remissions compared to multiply relapsed/refractory myeloma. As in the manuscript by Gu and colleagues, higher CD4+/CD8+ ratio at the time of leukapheresis has also been associated with response to cell therapy and thus, improved clinical outcomes. Furthermore, a significantly higher median CD4+/CD8+ ratio in newly diagnosed myeloma patients after initial therapy compared to relapsed/refractory myeloma has been reported. This suggests that leukapheresis for T cell products should be done soon after initial therapy and not when the patient is multiply relapsed (18, 19). In myeloma, CD4+ T cells are often times exhausted and outnumbered. Strategies that can rebuild T cell function should be investigated in clinical trials.