Michael Wang Laboratory

Principal Investigator: Michael Wang, M.D.

As a physician scientist, I am committed to advancing clinical and translational research to identify effective and safe treatments for patients with lymphoma and myeloma, concentrating mainly on mantle cell lymphoma (MCL). MCL is a rare subtype of non-Hodgkin lymphoma. My principal focus is on improving the care of patients with MCL through the actions of my multidisciplinary team of basic, translational and clinical research specialists. Together, we have worked on a host of preclinical studies and clinical trials devoted to patients with MCL. My lab is within the Lymphoma and Myeloma department, and is well funded through multiple funding mechanisms that include two NIH R01s and an R21, two CPRIT grants and two Leukemia and Lymphoma Society grants.

To promote continued research and improved treatment of MCL, I established the Mantle Cell Lymphoma Program of Excellence at MD Anderson Cancer Center as the world’s only program dedicated exclusively to MCL research and treatment. It is the largest institutional MCL group worldwide, with the greatest number of clinical trials aimed exclusively at MCL, the largest referral base and the most patients in the most clinical trials aimed specifically at MCL. Our clinical trials that resulted in the highest number of FDA approvals for MCL treatment: for the BTK inhibitors ibrutinib (Imbruvica), acalabrutinib (Calquence), and pirtobrutinib (Jaypirca) as well as the CAR T-cell therapy brexucabtagene autoleucel (Tecartus).

Our recent studies

Some recent studies in my lab

The role of MALT1 in BTK resistance. We discovered that MALT1, which lies approximately midway along the length of the BCR signaling pathway, is one of the overexpressed genes in ibrutinib-resistant MCL cells; meanwhile, expression of CARD11, which is just upstream of MALT1, is decreased in the setting of BTK inhibitor resistance. Inhibition or knockout of MALT1 markedly decreases MCL growth, regardless of ibrutinib sensitivity; meanwhile, CARD11 knockout only decreases MCL growth in ibrutinib-sensitive cells. Together, these findings suggest that MALT1 overexpression can drive ibrutinib resistance by bypassing both BTK and CARD11 signaling. Additionally, MALT1 inhibition or knockout markedly reduced tumor cell migration and dissemination. Importantly, co-targeting MALT1 (with safimaltib) and BTK (with pirtobrutinib) induced potent anti-MCL activity in ibrutinib-resistant MCL cell lines and patient-derived xenografts. Therefore, we concluded that MALT1 overexpression is associated with BTK inhibitor resistance in MCL. Accordingly, targeting abnormal MALT1 activity is a promising strategy to overcome BTK inhibitor resistance, and co-targeting of MALT1 and BTK should improve treatment efficacy and durability as well as patient outcomes.

The development of CAR-T therapy resistance. Chimeric antigen receptor (CAR) T-cell therapy has caused great excitement in oncology in general, and in mantle cell lymphoma. Here, T cells are extracted from the patient and genetically modified to recognize CD19 protein on the surface of the patients own B cells. After expansion, the CAR-T cells are then infused into the patient where they cause the destruction of B cells, including MCL tumor cells. I led the international ZUMA-2 trial of the CAR-T cell therapy brexucabtagene autoleucel (Tecartus, formerly KTE-X19) in relapsed/refractory MCL that showed a very impressive 93% response rate (Wang et al., N Engl J Med 382:1331 2020; Wang et al., J Clin Oncol 41:555, 2023). Crucially, while patient outcomes are historically very poor after ibrutinib relapse, roughly half of the patients continue to show positive results 3 years after CAR-T therapy. This therapy has been life-saving for a very desperate, heavily treated, and incurable population, and gained FDA approval through the Breakthrough Therapy designation. We just reported similarly impressive results for another CD19-directed CAR-T therapy, lisocabtagene maraleucel (Wang et al., J Clin Oncol in press, 2023).
Unfortunately, CAR-T therapy is not exempt from the development of resistance and relapse, and patients with CAR T-cell therapy relapse have poor outcomes. To determine the CAR-T therapy resistance mechanisms in MCL, we performed single-cell RNA sequencing on longitudinally collected samples from 15 CAR-T-treated patients, and multiplex cytokine profiling on 80 serial samples from 20 patients (Jiang et al., Molecular Cancer, 2022). After CAR-T therapy relapse, the proportion of cytotoxic T lymphocytes (CTLs) among non-tumor cells decreased, while the proportion of myeloid cells increased. The only checkpoint molecules that were significantly increased on exhausted T cells and CTLs after relapse was TIGIT. CTLs expanded during remission, and then contracted during relapse with upregulated TIGIT expression. Very unexpectedly, tumor cells also acquired TIGIT expression after relapse, leading to the enhanced interaction of tumor cell TIGIT with monocyte CD155/PVR. Additionally, myeloid-derived suppressor cells were enriched after relapse with elevated expression of activation markers, and extracellular chemokines, soluble checkpoint inhibitors, and soluble receptors were decreased during remission but elevated after relapse. All together, our data demonstrate that multiple tumor-intrinsic and -extrinsic factors are associated with T-cell suppression and CAR-T relapse. Among these, TIGIT appears to be the central player given its elevated expression after CAR-T relapse in not only CTLs but also MCL cells. The acquisition of TIGIT expression on tumor cells is MCL-specific and has not been reported in other CAR T-treated diseases. Together, our data suggest that co-targeting TIGIT may prevent CAR-T therapy relapse and thus promote long-term progression-free survival in MCL patients.

Potential treatments for CAR-T therapy resistance. Thus far, there is no specific designated therapy for patients with CAR-T therapy relapse, and the development of efficacious therapies is critically needed. In another study (Jiang et al., Journal of Hematology and Oncology, 2021), we found that while the receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed across most MCL cells, it is significantly elevated in CAR-T therapy relapsed MCL tumors. To see whether this aberrant ROR1 expression contributed to CAR-T resistance, we targeted ROR1 using the antibody-drug conjugate VLS-101, comprising an anti-ROR1 antibody conjugated by a linker to the toxin monomethyl auristatin E. VLS-101 had potent anti-MCL activity in vitro in ROR1-expressing MCL cell lines and ex vivo in primary patient samples. Importantly, VLS-101 induced tumor regression in PDXs that were resistant to CAR-T therapy, ibrutinib, and/or venetoclax (Wang et al., New England Journal of Medicine Evidence, 2022). These data indicate that targeting of ROR1 is a viable approach in the treatment of ROR1-positive MCL tumors, especially those with failure to prior therapies.

Combination therapies against multiple forms of resistance. Inhibitors of BTK reduce tumor growth largely by reducing tumor cell proliferation; inhibitors of the apoptosis regulator BCL-2, which is highly expressed in MCL, reduce tumor growth largely by increasing tumor cell death. The combination of the BTK inhibitor ibrutinib and the BCL-2 inhibitor venetoclax produced favorable complete response rates in patients with MCL (Wang et al., Blood, 2023). Replacement of ibrutinib in this combination with the novel noncovalent BTK inhibitor pirtobrutinib is an interesting idea, given that pirtobrutinib has high target coverage, low off-target inhibition, and promising efficacy, even in patients with MCL who had relapsed after covalent BTK inhibitor treatment. Accordingly, we investigated the combination of pirtobrutinib and venetoclax in MCL models in vitro and in vivo to provide proof of concept for further exploration in the clinic (Liu et al., Haematologica, 2023). In PDXs from a patient with dual ibrutinib and CAR-T therapy resistance, the combination had greater antitumor efficacy than either monotherapy, very dramatically increasing survival even after treatment withdrawal. A Phase II clinical trial (NCT05529069) based on this study has been activated here.