Preclinical Model Suggests Efficacy of Combining Capivasertib With Venetoclax Against DLBCL

Combining capivasertib, an AKT inhibitor, with venetoclax, an BCL-2 inhibitor, provoked promising responses in patients with diffuse large B-cell lymphoma (DLBCL), according to a study in Nature.¹ Researchers conducted an in vitro combination screen across a panel of 26 DLCBL cell lines.

“Here we show for the first time that combination of capivasertib and venetoclax has potential to provide broad activity in PTEN-wildtype and PTEN-deficient DLBCL preclinical models. This combination causes death of DLBCL cell lines in vitro and is highly efficacious in various lymphoma models in vivo,” the authors wrote. “Concurrent dosing of capivasertib and venetoclax is necessary for optimal anti-tumoral activity and more importantly, we found that combination efficacy and disease control persists following adjustments to either dose level or frequency of venetoclax.”

Typical therapy for DLBCL largely consists of RCHOP and, recently, a modified regimen that substitutes vincristine for polatuzumab vedotin. | Image Credit: © Seventyfour - stock.adobe.com

Capivasertib and venetoclax rapidly induced caspase and PARP cleavage in GCB DLBCL PTEN wildtype cell lines, and in those with PTEN mutations or reduced PTEN protein. As a result, tumor growth was inhibited in DLBCL cell lines and patient-derived xenograft lymphoma models. Adding rituximab enhanced the durability of the capivasertib and venetoclax responses in rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)–refractory DLBCL in vivo models.

The panel of 7 ABC, 14 GCB, and 5 unclassified DLBCL cell lines had heterogenous levels of AKT pathway activation, PTEN protein, and antiapoptotic cell death proteins BCL-2, BCL-2-like 1 (BCL-XL), and MCL-1 expression.

The study found that capivasertib monotherapy treatment is effective in GCB DLBCL cell lines and xenograft models. Monotherapy anti-proliferative responses (GI50) with capivasertib were enriched in PTEN deficient cell lines. By contrast, venetoclax monotherapy resulted in cell death (AC50) in GCB-DLCBL and ABC-DLBCL subtypes. Capivasertib and venetoclax demonstrated strong activity as determined by the Loewe score, mainly in the GCB-DLCBL subcategory, regardless of PTEN status. However, certain pAKT and BCL-2 positive lines were insensitive to the combination.

After combination treatment, sensitive PTEN-wild-type (SUDHL-4) and PTEN-deficient (WSU-DLCL2) GCB-DLBCL and insensitive PTEN wild-type (TMD8, OCI-LY10, U2932) ABC-DLBCL cell lines were evaluated. Combination treatment induced rapid induction of caspase 3/7 within 4 hours, which was maintained at 24 hours in the SUDHL-4 and WSU-DLCL2 cell lines. Meanwhile, the insensitive PTEN wildtype cells lacked caspase induction.

Researchers seeded 1000 to 8000 cells per well, in a 384-well plate. Twenty-four hours later, plating cells were treated for 120 hours with a 6-point dose response (0.03–3 μM) in a combination matrix (6 × 6), using an Echo 555 acoustic dispenser (Labcyte). Cell proliferation vs cell death was determined by comparing day 0 (pretreatment) and 72 or 120 hours (post treatment). Percentage growth was calculated based on the live cell number. Researchers performed DNA fingerprinting short tandem repeat authentication of cell lines.

Typical therapy for DLBCL largely consists of RCHOP and, recently, a modified regimen that substitutes vincristine for polatuzumab vedotin (pola-R-CHP).

“Despite these recent improvements in first line therapies, relapsed/refractory DLBCL patients still require novel treatment regimens,” the authors wrote.

DLBCL is the most common lymphoma subtype worldwide, corresponding to roughly 30% to 40% of cases, according to the study. DLBCL is a heterogenous B-cell malignancy driven by genetic and epigenetic changes that regulate cell growth, survival, and differentiation.

In the US, DLBCL is the most common type of non-Hodgkin lymphoma (NHL) and accounts for about 22 percent of newly diagnosed cases of B-cell NHL, according to the Lymphoma Research Foundation.² More than 18,000 Americans are diagnosed with DLBCL each year.

“These findings provide preclinical evidence for the rational treatment combination of AKT and BCL-2 inhibitors using capivasertib and venetoclax respectively alongside anti-CD20 antibody supplementation for treatment of patients with DLBCL,” the authors wrote.¹

References

1. Willis BS, Mongeon K, Dry H, et al. Potent combination benefit of the AKT inhibitor capivasertib and the BCL-2 inhibitor venetoclax in diffuse large B cell lymphoma. Nature. 2024. doi: 10.1038/s41375-024-02401-9
2. What is Lymphoma? Lymphoma Research Foundation. Accessed Sept. 25, 2024. https://lymphoma.org/understanding-lymphoma/aboutlymphoma/nhl/dlbcl/