P1, N=47, Active, not recruiting, Sanofi | Trial completion date: Aug 2024 --> Mar 2025

P1, N=53, Terminated, Hoffmann-La Roche | N=200 --> 53 | Trial completion date: Apr 2025 --> Jul 2024 | Recruiting --> Terminated | Trial primary completion date: Apr 2025 --> Jul 2024; The study was terminated due to sponsor portfolio re-alignment.

P1/2, N=42, Recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Jun 2024 --> Jun 2026

P1/2, N=115, Recruiting, ModeX Therapeutics, An OPKO Health Company | Not yet recruiting --> Recruiting

Vactoserib, a TGF-β inhibitor, was able to mitigate this effect and restore sensitivity to SAR442257 in these experiments. In conclusion, SAR442257 has high potential for enhancing TC cytotoxicity by co-targeting CD38 and CD28 on MM and CD3/CD28 on T cells.

P1, N=47, Active, not recruiting, Sanofi | Trial completion date: Apr 2024 --> Aug 2024

P1/2, N=612, Recruiting, Regeneron Pharmaceuticals | N=326 --> 612 | Trial primary completion date: Jan 2027 --> Apr 2027

We developed a bispecific CD19-targeted CD28 agonist (RG6333, CD19-CD28) to enhance the efficacy of glofitamab and similar TCBs by delivering signal 2 to tumor-infiltrating T cells. CD19-CD28 distinguishes itself from the superagonistic antibody TGN1412, as its activity requires the simultaneous presence of a TCR signal and CD19 target binding...Our findings highlight CD19-CD28 as a safe and highly efficacious off-the-shelf combination partner for glofitamab, similar TCBs, and other costimulatory agonists. CD19-CD28 is currently in a Phase 1 clinical trial in combination with glofitamab.

P1, N=47, Active, not recruiting, Sanofi | Recruiting --> Active, not recruiting | Trial completion date: Apr 2026 --> Apr 2024

P1/2, N=370, Recruiting, Regeneron Pharmaceuticals | N=199 --> 370 | Trial completion date: Aug 2026 --> Jan 2027 | Trial primary completion date: Aug 2026 --> Jan 2027

P1, N=44, Terminated, Sanofi | N=200 --> 44 | Trial completion date: Feb 2026 --> Jan 2024 | Recruiting --> Terminated | Trial primary completion date: Feb 2026 --> Jan 2024; Sponsor's decision. Termination decision unrelated to safety profile

P1/2, N=115, Not yet recruiting, ModeX Therapeutics, An OPKO Health Company

P1/2, N=42, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

This study is ongoing and currently open to enrollment. Clinical trial information: NCT04626635.

P1, N=110, Recruiting, Janssen Research & Development, LLC | Not yet recruiting --> Recruiting

SAR442257 also induced CD25 and CD69 expression on normal T-cells suggesting efficient T-cell activation, (data not shown). Conclusion Altogether, this study shows that 1) most PTCL cells express at least CD28 or CD38, and 2) SAR442257 can efficiently kill malignant PTCL cells, while ensuring effective T-cell activation; In view of these results, clinical investigation of SAR442257 in PTCL is warranted.

Aims: To evaluate CD38 as a potential therapeutic target in AML, and to determine the mode of action and preclinical efficacy of isatuximab (an IgG1 anti-CD38 mAb) and SAR442257, which is a new CD38/CD28xCD3 trispecific TCE. CD38 is widely present in blasts from older AML patients but nearly half show heterogeneous expression. While isatuximab-driven ADCC in AML cell lines and primary samples is dependent on CD38 density in tumor cells, the CD38/CD28xCD3 TCE exerted its anti-tumor efficacy regardless of CD38 density. Thus, AML patients expressing both high and low/heterogenous levels of CD38 could benefit from T cell based immunotherapeutic strategies targeting CD38.

Aim: Evaluate a CD38/CD28xCD3 trispecific TCE (SAR442257) as a potential therapeutic agent in the RRMM setting...First, we observed that, contrary to isatuximab and daratumumab, CD38/CD28xCD3 TCE did not reduce surface CD38 levels in the MOLP 8, RPMI 8226 and KMS 12 BM cell lines... We observed a reduction in CD38 levels in MMPC and an impaired cytotoxic activity of NK cells in RRMM patients previously exposed to anti-CD38 mAbs. We propose a second targeting of CD38 using T-cell-based immunotherapeutic agents whose efficacy depends less on CD38 antigen density, especially after longer washout periods, as a potential therapeutic strategy in the RRMM setting.

P1/2, N=769, Recruiting, Regeneron Pharmaceuticals | N=434 --> 769 | Trial completion date: Apr 2026 --> Dec 2026 | Trial primary completion date: Apr 2026 --> Aug 2026

P1, N=110, Not yet recruiting, Janssen Research & Development, LLC

P1/2, N=42, Not yet recruiting, M.D. Anderson Cancer Center

P1, N=200, Recruiting, Hoffmann-La Roche | Trial completion date: Apr 2024 --> Apr 2025 | Trial primary completion date: Apr 2024 --> Apr 2025

P1, N=44, Recruiting, CytoCares Inc

SAR442257 has increased binding capacity for RRMM due to CD38 and CD28 targets and demonstrated activity on RRMM cells as reasonable alternative for future RRMM therapy approach.

P1/2, N=297, Recruiting, Regeneron Pharmaceuticals | N=216 --> 297 | Trial completion date: Feb 2025 --> Jul 2026 | Trial primary completion date: Feb 2024 --> Aug 2025

Nature. 2022; 603:328-334.

P1, N=57, Recruiting, Sanofi | Trial completion date: Jun 2025 --> Apr 2026

This Phase 1, open-label, first-in-human study will assess the safety and tolerability of REGN5837 in combinationwith odronextamab in patients with R/R aggressive B-NHL.

CD19 CAR T-cells were constructed from PBMCs of rrLBCL patients obtained at the time of apheresis using a construct like axicabtagene ciloleucel (axi-cel). The tumor microenvironment of CAR T refractory rrLBCL is enriched in clonally expanded and terminally exhausted CD8 T-cells expressing CD38. The CD38/CD28xCD3 trispecific antibody SAR442257 boosted CAR T-cell activity through recognition of CD38 on the tumor, costimulation of CAR T-cells, and induced fratricide of CD38+ T-cells; resulting in superior tumor cell killing. In addition, SAR442257 allowed CD19 CAR T-cells to kill CD19- /CD38+ LBCL cells.

The superagonistic monoclonal anti-human CD28 antibody (IgG4κ) TGN1412 was used as comparator. Activity is maintained while it allows well tailorable dose response with reduced cytokine release. Compounds are currently in extensive pre-clinical assessment 999

In translating Cbl-b inhibitors to clinic, we propose specific gene expression profiles that may identify patient populations most likely to benefit. Overall, novel Cbl-b inhibitors provide antigen-specific immune stimulation and are a promising therapeutic tool in the field of immuno-oncology.

No abstract available

Across the different study parts, the treatment schedule is consistent with a single fixed dose of obinutuzumab (1000mg intravenously) given at least 3 days prior to glofitamab step up dosing (2.5/10/30mg)...Commencement of part 4, the expansion phase, including decision on the RO7443904 dose will be guided by a concerted review of safety, PK, and PD data from all dose escalation parts...Figure 1: Efficacy study in a disseminated DLBCL model in humanized NSG mice treated with monotherapy of glofitmab (0.15 mg/kg) or CD19-CD28 (1 mg/kg) as well as with a combination of both. The data suggest a strong anti-tumor effect when both agents are combined.

P1, N=200, Recruiting, Sanofi | Trial completion date: Jun 2025 --> Sep 2025 | Trial primary completion date: Jun 2025 --> Sep 2025

P1, N=184, Recruiting, Sanofi | Trial completion date: Nov 2025 --> Jun 2025 | Trial primary completion date: Nov 2025 --> Jun 2025

PBMCs from healthy donors were cultured for 10 days with CON medium (unstimulated control); EX media, CON with recombinant human interleukin-2 (rhIL-2) and zoledronate; and EX28 media, CON with rhIL-2, zoledronate, and CD3/CD28 activator. The expanded γδ T cells were isolated by magnetic cell separation or fluorescence-activated cell sorting, cultured with two OS cell lines (KHOS/NP and MG-63) at various cell ratios with or without doxorubicin or ifosfamide, and analyzed for cytotoxicity and cytokine secretion...The expanded γδ T cells exhibited potent in vitro cytotoxicity against OS in a ratio- and time-dependent manner. The γδ T cells may enhance the effect of chemotherapeutic agents against OS and may be a new treatment strategy, including chemo-immunotherapy, for OS.

Exclusion criteria include recent biologic therapy (7 days); approved conventional therapy (except biologics or immunotherapy) <3 weeks (wks) or investigational agents <4 wks prior to first study dose; and anti–PD-L1 therapy <5 T 1/2 prior to first study dose. Key exploratory endpoints are correlation between clinical efficacy endpoints and baseline protein expression levels of MUC16 and PD-L1. Results and Discussions NA Conclusion NA

Here, we demonstrate that T cells infiltrating mouse mammary carcinomas that are therapeutically controlled by NAM also express multiple markers of late-stage activation. Taken together, these findings lend additional support to the notion that the antineoplastic effects of NAM involve at least some degree of restored cancer immunosurveillance.

The 0.1 mg/kg cohorts have been completed without DLT. Enrollment to the 0.3 mg/kg cohorts began in September 2021.

P1, N=184, Recruiting, Sanofi | Trial completion date: Jun 2025 --> Nov 2025 | Trial primary completion date: Jun 2025 --> Nov 2025

The resulting TAA-CD28 κλ bodies can enhance the antitumor response induced by CD3-retargeting bsAbs via the induction of T cell proliferation and activation, increased cytokine secretion and boosted anti-tumoral cytotoxicity. Other anti-TAA arms are being explored, to expand the panel of TAAs that could be easily paired with our anti-CD28 platform arms.