CD47-SIRPα blocking-based immunotherapy:Current and prospective therapeutic strategies

BACKGROUND: The CD47‐signal regulatory protein alpha (SIRPα) ‘don't eat me’ signalling axis is perhaps the most prominent innate immune checkpoint to date. However, from initial clinical trials, it is evident that monotherapy with CD47‐SIRPα blocking has a limited therapeutic effect at the maximum tolerated dose. Furthermore, treatment is associated with severe side effects, most notably anaemia, that are attributable to the ubiquitous expression of CD47. Nevertheless, promising clinical responses have been reported upon combination with the tumour‐targeting antibody rituximab or azacytidine, although toxicity issues still hamper clinical application. MAIN BODY: Here, we discuss the current state of CD47‐SIRPα blocking therapy with a focus on limitations of current strategies, such as depletion of red blood cells. Subsequently, we focus on innovations designed to overcome these limitations. These include novel antibody formats designed to selectively target CD47 on tumour cells as well as tumour‐targeted bispecific antibodies with improved selectivity. In addition, the rationale and outcome of combinatorial approaches to improve the therapeutic effect of CD47 blockade are discussed. Such combinations include those with tumour‐targeted opsonizing antibodies, systemic therapy, epigenetic drugs, other immunomodulatory T‐cell‐targeted therapeutics or dual immunomodulatory CD47 bispecific antibodies. CONCLUSION: With these advances in the design of CD47‐SIRPα‐targeting therapeutic strategies and increasing insight into the mechanism of action of this innate checkpoint, including the role of adaptive immunity, further advances in the clinical application of this checkpoint can be anticipated

The Implementation of TNFRSF Co-Stimulatory Domains in CAR-T Cells for Optimal Functional Activity

SIMPLE SUMMARY: Members of the Tumor Necrosis Factor Receptor Superfamily (TNFRSF) provide crucial co-stimulatory signals to many if not all immune effector cells. With distinct and unique functional features on multiple types of immune effector cells, the co-stimulatory activity of TNFRSF members is being implemented in the tailoring of Chimeric Antigen Receptor (CAR) T cell activity for cancer therapy. This integration of intracellular TNFRSF stimulatory domains into a CAR provides a unique signaling output. Here, we highlight the rationale and summarize the current evidence for the application and the unique attributes of co-stimulatory signaling by TNFRSF members (4-1BB; OX40; CD40; CD27; GITR; HVEM) in CAR-T therapy. ABSTRACT: The Tumor Necrosis Factor Receptor Superfamily (TNFRSF) is a large and important immunoregulatory family that provides crucial co-stimulatory signals to many if not all immune effector cells. Each co-stimulatory TNFRSF member has a distinct expression profile and a unique functional impact on various types of cells and at different stages of the immune response. Correspondingly, exploiting TNFRSF-mediated signaling for cancer immunotherapy has been a major field of interest, with various therapeutic TNFRSF-exploiting anti-cancer approaches such as 4-1BB and CD27 agonistic antibodies being evaluated (pre)clinically. A further application of TNFRSF signaling is the incorporation of the intracellular co-stimulatory domain of a TNFRSF into so-called Chimeric Antigen Receptor (CAR) constructs for CAR-T cell therapy, the most prominent example of which is the 4-1BB co-stimulatory domain included in the clinically approved product Kymriah. In fact, CAR-T cell function can be clearly influenced by the unique co-stimulatory features of members of the TNFRSF. Here, we review a select group of TNFRSF members (4-1BB, OX40, CD27, CD40, HVEM, and GITR) that have gained prominence as co-stimulatory domains in CAR-T cell therapy and illustrate the unique features that each confers to CAR-T cells

New treatment for patients with therapy-resistant lymphoma:CD19-targeted chimeric antigen receptor (CAR) T-cell therapy

The prognosis of patients with diffuse large B-cell lymphoma a primary refractory disease or relapsed within 12 months after autologous hematopoietic cell transplantation is poor with a median survival of only 6 months. With the new CD19-directed CAR T-cell therapy, 40% of the patients still achieve a long-term remission. However, this new treatment does bring new challenges such as bridging the time during the CAR T-cell product time, and recognition of treatment-related side effects such as cytokine release syndrome or neurotoxicity. Therefore, treatment by a dedicated, multidisciplinary team is necessary. Future research will focus on extending CAR T-cell therapy to other diseases and improve treatment in non-responsiveness or resistance to CAR-T cell therapy

Navitoclax Most Promising BH3 Mimetic for Combination Therapy in Hodgkin Lymphoma

The treatment of young patients with Hodgkin lymphoma (HL) is often successful but a significant proportion of patients suffers from late toxicity. In the current era there are new opportunities for less toxic and more targeted treatment options. In this respect, the anti-apoptotic pathway is an attractive target since Hodgkin tumor cells abundantly express components of this pathway. We measured the effect of BH3 mimetics that interfere with anti-apoptotic proteins in cell lines, also in combination with the standard of care chemotherapeutic doxorubicin and the recently discovered preclinically active tamoxifen. Several anti-apoptotic BCL-2 family proteins were expressed in each case (n = 84) and in HL cell lines (n = 5). Cell lines were checked for sensitivity to BH3 mimetics by BH3 profiling and metabolic assays and monotherapy was only partially successful. Doxorubicin was synergistic with a BCL-XL inhibitor and BCL2/XL/W inhibitor navitoclax. Tamoxifen that targets the estrogen receptor β present in the mitochondria of the cell lines, could induce cell death, and was synergistic with several BH3 mimetics including/as well as navitoclax. In conclusion, targeting the anti-apoptotic pathway by the triple inhibitor navitoclax in combination with doxorubicin or tamoxifen is a promising treatment strategy in HL

Extranodal Natural Killer/T-cell Lymphoma, Nasal Type:Diagnosis and Treatment

The aggressive lymphoma, extranodal natural killer/T-cell lymphoma-nasal type, is strongly associated with Epstein-Barr virus (EBV) and is most common in Asia and in South and Central America. By contrast, incidence is low in the United States and Europe, where extranodal natural killer/T-cell lymphoma represents only 0.2%-0.4% of all newly diagnosed non-Hodgkin lymphomas. At diagnosis, it is important to test for EBV DNA in plasma by polymerase chain reaction and to carry out positron emission tomography/computer tomography and magnetic resonance imaging of the nasopharynx. In stage I/II disease, radiotherapy is the most important treatment modality, but in high-risk stage I/II disease (stage II, age > 60 y, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group performance score ≥2, primary tumor invasion), it should be combined with chemotherapy. The most optimal responses are reached with nonmultidrug resistance-based therapy (eg, asparaginase- or platinum-based therapy). Therapeutic approaches consist of either platinum-based concurrent chemoradiotherapy or sequential chemoradiotherapy. The minimum dose of radiotherapy should be 50-56 Gy. Treatment of stage III/IV disease consists of 3 cycles of chemotherapy followed by autologous hematopoietic cell transplantation. Allogeneic hematopoietic cell transplantation should only be considered in case of relapsed disease or after difficulty reaching complete remission. During treatment and follow-up, plasma EBV levels should be monitored as a marker of tumor load

Semi-automated 18F-FDG PET segmentation methods for tumor volume determination in Non-Hodgkin lymphoma patients:a literature review, implementation and multi-threshold evaluation

In the treatment of Non-Hodgkin lymphoma (NHL), multiple therapeutic options are available. Improving outcome predictions are essential to optimize treatment. The metabolic active tumor volume (MATV) has shown to be a prognostic factor in NHL. It is usually retrieved using semi-automated thresholding methods based on standardized uptake values (SUV), calculated from 18F-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG PET) images. However, there is currently no consensus method for NHL. The aim of this study was to review literature on different segmentation methods used, and to evaluate selected methods by using an in house created software tool. A software tool, MUltiple SUV Threshold (MUST)-segmenter was developed where tumor locations are identified by placing seed-points on the PET images, followed by subsequent region growing. Based on a literature review, 9 SUV thresholding methods were selected and MATVs were extracted. The MUST-segmenter was utilized in a cohort of 68 patients with NHL. Differences in MATVs were assessed with paired t-tests, and correlations and distributions figures. High variability and significant differences between the MATVs based on different segmentation methods (p < 0.05) were observed in the NHL patients. Median MATVs ranged from 35 to 211 cc. No consensus for determining MATV is available based on the literature. Using the MUST-segmenter with 9 selected SUV thresholding methods, we demonstrated a large and significant variation in MATVs. Identifying the most optimal segmentation method for patients with NHL is essential to further improve predictions of toxicity, response, and treatment outcomes, which can be facilitated by the MUST-segmenter

Heterogeneous Pattern of Dependence on Anti-Apoptotic BCL-2 Family Proteins upon CHOP Treatment in Diffuse Large B-Cell Lymphoma

Expression of the anti-apoptotic B-cell lymphoma 2 (BCL-2) protein in patients with diffuse large B-cell lymphoma (DLBCL) strongly correlates with resistance to standard therapy with cyclophosphamide, vincristine, doxorubicin, prednisolone, and rituximab (R-CHOP). Although studies focus mainly on the contribution of BCL-2, here we also investigate the contribution of other anti-apoptotic proteins to CHOP-therapy resistance in DLBCL. Functional dynamic BCL-2 homology (BH)3 profiling was applied to DLBCL cell lines upon CHOP treatment or single CHOP compounds. Cell-specific anti-apoptotic dependencies were validated with corresponding BH3-mimetics. We found high expression of anti-apoptotic BCL-2, MCL-1, and BCL-XL in DLBCL cell lines and patients. CHOP treatment resulted in both enhanced and altered anti-apoptotic dependency. Enhanced sensitivity to different BH3-mimetics after CHOP treatment was confirmed in specific cell lines, indicating heterogeneity of CHOP-induced resistance in DLBCL. Analysis of single CHOP compounds demonstrated that similar changes could also be induced by doxorubicin or vincristine, providing evidence for clinical combination therapies of doxorubicin or vincristine with BH3-mimetics in DLBCL. In conclusion, we show for the first time that CHOP treatment induces increased anti-apoptotic dependency on MCL-1 and BCL-XL, and not just BCL-2. These results provide new perspectives for the treatment of CHOP-resistant DLBCL and underline the potential of BH3 profiling in predicting therapy outcomes