Copanlisib in Combination With Anti‐pd‐1 Induces Regression in Animal Tumor Models Insensitive or Resistant to the Monotherapies of Pi3k and Checkpoint Inhibitors

Liu, N.; Haike, Katja; Glaeske, Sarah; Paul, Joseph; Mumberg, Dominik; Kreft, Bertolt; Ziegelbauer, Karl

doi:10.1002/hon.2438_123

Cited by 6 publications

(5 citation statements)

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“…However, a more detailed subset analysis of CD4 þ T-lymphocytes was not performed (the FOXP3 þ antigen was not evaluated), limiting conclusive interpretations on which Treg populations may be modulated by copanlisib activity. Together with the high PI3K isoform expression observed in patients with lymphoma, these results support future validation studies and provide rationale for clinical studies of copanlisib in combination with immune checkpoint inhibitors (31).…”

Section: Discussionsupporting

confidence: 69%

On-Target Pharmacodynamic Activity of the PI3K Inhibitor Copanlisib in Paired Biopsies from Patients with Malignant Lymphoma and Advanced Solid Tumors

Morschhauser

Machiels

Salles

et al. 2020

Molecular Cancer Therapeutics

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The PI3K inhibitor copanlisib has efficacy and manageable safety in patients with indolent lymphoma and solid tumors. Pharmacodynamic effects relative to copanlisib dose and plasma exposure were evaluated. Patients with lymphoma or solid tumors received copanlisib 0.4 or 0.8 mg/kg on days 1, 8, and 15 of a 28-day cycle. Primary variables were maximum changes in phosphorylated AKT (pAKT) levels in platelet-rich plasma (PRP) and plasma glucose. Other evaluations included PI3K signaling markers and Tlymphocytes in paired tumor biopsies, the relationship between estimated plasma exposure and pharmacodynamic markers, response, and safety. Sixty-three patients received copanlisib. PRP pAKT levels showed sustained reductions from baseline following copanlisib [median inhibition: 0.4 mg/kg, 73.8% (range À94.9 to 144.0); 0.8 mg/kg, 79.6% (range À96.0 to 408.0)]. Tumor pAKT was reduced versus baseline with copanlisib 0.8 mg/kg in paired biopsy samples (P < 0.05). Dose-related transient plasma glucose elevations were observed. Estimated copanlisib plasma exposure significantly correlated with changes in plasma pAKT and glucose metabolism markers. There were two complete responses and six partial responses; seven of eight responders received copanlisib 0.8 mg/kg. Adverse events (all grade) included hyperglycemia (52.4%), fatigue (46.0%), and hypertension (41.3%). Copanlisib demonstrated dosedependent pharmacodynamic evidence of target engagement and PI3K pathway modulation/inhibition in tumor and immune cells. Results support the use of copanlisib 0.8 mg/kg (or flat-dose equivalent of 60 mg) in solid tumors and lymphoma, and provide a biomarker hypothesis for studies of copanlisib combined with immune checkpoint inhibitors (NCT03711058).

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Section: Discussionsupporting

confidence: 69%

On-Target Pharmacodynamic Activity of the PI3K Inhibitor Copanlisib in Paired Biopsies from Patients with Malignant Lymphoma and Advanced Solid Tumors

Morschhauser

Machiels

Salles

et al. 2020

Molecular Cancer Therapeutics

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“…The last observation is supported by data indicating a selective and concentration-dependent suppression of Treg cells but not of the proliferation of CD8+ T-cells [ 31 ]. Suppression of Tregs in syngeneic tumors is also reported with the PI3Kα/δ inhibitor copanlisib [ 92 ], and with KA2237 [ 38 ]. In an in vivo mammary tumor model, PI3Kδ blockade leads tumors to be divided in “non-regressors”, in which tumor growth rate is reduced but tumors continue to grow, and “regressors” where tumors shrink.…”

Section: Targeting Pi3kδ and Treg In Lymphomasmentioning

confidence: 95%

“…In this context, CD8+ CTL can still mediate anti-tumor activity, although an altered balance between regulatory and effector CD4+ T-cells, with effector cells that prevail. Pharmacological targeting of PI3Kδ lead to similar changes compared to genetical inhibition, such as suppression of tumor growth and reduction of immunosuppression, in many cancer models [ 22 , 31 , 82 , 86 , 92 , 93 , 94 , 95 , 96 ]. The PI3Kδ inhibitor parsaclisib has in vivo antitumor activity against the A20 mouse lymphoma cell lines despite no in vitro anti-tumor activity [ 96 ].…”

Section: Targeting Pi3kδ and Treg In Lymphomasmentioning

confidence: 99%

“…Finally, data collected in syngeneic mouse models mostly suggest that PI3Kδ inhibitors show synergism with immune checkpoint modulators [ 22 , 31 , 92 ]. However, there are also data demonstrating an important suppression of CD8+ T-cells maturation and killing capacity, antagonizing the effect due to immune checkpoint blockade [ 100 ].…”

Section: Targeting Pi3kδ and Treg In Lymphomasmentioning

confidence: 99%

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PI3Kδ Inhibitors as Immunomodulatory Agents for the Treatment of Lymphoma Patients

Tarantelli

Argnani

Zinzani

et al. 2021

Cancers

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The development of small molecules able to block specific or multiple isoforms of phosphoinositide 3-kinases (PI3K) has already been an active field of research for many years in the cancer field. PI3Kδ inhibitors are among the targeted agents most extensively studied for the treatment of lymphoma patients and PI3Kδ inhibitors are already approved by regulatory agencies. More recently, it became clear that the anti-tumor activity of PI3K inhibitors might not be due only to a direct effect on the cancer cells but it can also be mediated via inhibition of the kinases in non-neoplastic cells present in the tumor microenvironment. T-cells represent an important component of the tumor microenvironment and they comprise different subpopulations that can have both anti- and pro-tumor effects. In this review article, we discuss the effects that PI3Kδ inhibitors exert on the immune system with a particular focus on the T-cell compartment.

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“…One potential strategy to treat PTEN-deficient mCRPC is inhibition of the dysregulated activity of the PI3K signaling cascade, which drives increased aerobic glycolysis via the Warburg effect (27) and enhanced proliferation (33), survival (34), and metastasis (25). However, preclinical and clinical trial data has demonstrated that PI3K inhibitors are ineffective as single agents in the majority of solid tumor malignancies, independent of PTEN status (35)(36)(37)(38).…”

Section: Introductionmentioning

confidence: 99%

Reversal of lactate and PD-1-mediated macrophage immunosuppression controls growth of PTEN/p53-deficient prostate cancer

Chaudagar

Hieromnimon

Khurana

et al. 2022

Preprint

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PTEN loss-of-function occurs in approximately 50% of mCRPC patients, and is associated with a poor prognosis, therapeutic outcomes and resistance to immune-checkpoint inhibitors. Recent clinical studies demonstrated that dual PI3K/AKT pathway inhibition and androgen axis blockade led to a modest improvement in progression-free survival of PTEN-deficient mCRPC patients, but the mechanistic basis for this limited efficacy is unknown. To elucidate potential resistance mechanism(s), we performed co-clinical trials in a prostate-specific PTEN/p53-deficient genetically-engineered mouse model, and discovered that the recruitment of PD-1-expressing tumor-associated macrophages (TAM) thwarts the phagocytosis-mediated anti-tumor efficacy of androgen deprivation therapy (ADT)/PI3K inhibitor (PI3Ki) combination. Strikingly, we observed a TAM-dependent ∼3-fold enhancement in the overall response rate with the addition of PD-1 antibody (aPD-1) to ADT/PI3Ki combination therapy. Mechanistically, decreased lactate production from PI3Ki-treated tumor cells suppressed histone lactylation (H3K18lac) within TAM, resulting in their phagocytic activation, which was augmented by concurrent ADT/aPD-1 treatment. Consistent with our murine observations, single cell RNA-sequencing analysis of human metastatic PC samples revealed a direct correlation between high glycolytic activity and phagocytosis suppression. Critically, feedback activation of Wnt/β-catenin signaling observed in non-responder mice following ADT/PI3Ki/aPD-1 combination treatment, restored lactate-mediated H3K18lac and suppressed phagocytosis within macrophages. Altogether, these data suggest that reversal of lactate and PD-1-mediated TAM immunosuppression by PI3Ki and aPD-1, respectively, controls tumor growth in combination with ADT, and warrants further clinical investigation in PTEN/p53-deficient mCRPC patients.One Sentence SummaryInhibition of tumor-cell intrinsic lactate production suppresses PTEN/p53-deficient prostate cancer growth via macrophage activation/phagocytosis

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Copanlisib in Combination With Anti‐pd‐1 Induces Regression in Animal Tumor Models Insensitive or Resistant to the Monotherapies of Pi3k and Checkpoint Inhibitors

Cited by 6 publications

References 0 publications

On-Target Pharmacodynamic Activity of the PI3K Inhibitor Copanlisib in Paired Biopsies from Patients with Malignant Lymphoma and Advanced Solid Tumors

On-Target Pharmacodynamic Activity of the PI3K Inhibitor Copanlisib in Paired Biopsies from Patients with Malignant Lymphoma and Advanced Solid Tumors

PI3Kδ Inhibitors as Immunomodulatory Agents for the Treatment of Lymphoma Patients

Reversal of lactate and PD-1-mediated macrophage immunosuppression controls growth of PTEN/p53-deficient prostate cancer

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