Combining PARP inhibition and immune checkpoint blockade in ovarian cancer patients: a new perspective on the horizon?

Musacchio, Lucia; Cicala, Carlo Maria; Camarda, Floriana; Ghizzoni, Viola; Giudice, Elena; Carbone, Maria Vittoria; Ricci, Caterina; Perri, Maria Teresa; Tronconi, Francesca; Gentile, Marica; Salutari, Vanda; Scambia, Giovanni; Lorusso, Domenica

doi:10.1016/j.esmoop.2022.100536

Cited by 18 publications

(13 citation statements)

References 73 publications

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“…Of note, inhibition of PARP1 does not only have cancer cell-autonomous effects but also stimulates T lymphocyte-mediated anticancer immune response through yet-to-be-elucidated mechanisms [ 6 , 12 , 15 ]. Thus, combining PARP1 inhibition with immune checkpoint blockade holds promise for the treatment of ovarian cancer patients [ 16 ].…”

Section: Parp1 In Dna Repair: a Target For Anticancer Drugsmentioning

confidence: 99%

Poly(ADP-ribose) polymerase-1 and its ambiguous role in cellular life and death

Castedo¹,

Lafarge²,

Kroemer³

2023

CST

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The deletion of the gene coding for poly(ADPribose) polymerase-1 (PARP1) or its pharmacological inhibition protects mice against cerebral ischemia and Parkinson’s disease. In sharp contrast, PARP1 inhibitors are in clinical use for the eradication of vulnerable cancer cells. It appears that excessive PARP1 activation is involved in a specific cell death pathway called parthanatos, while inhibition of PARP1 in cancer cells amplifies DNA damage to a lethal level. Hence, PARP1 plays a context-dependent role in cell fate decisions. In addition, it appears that PARP1 plays an ambiguous role in organismal aging.

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Section: Parp1 In Dna Repair: a Target For Anticancer Drugsmentioning

confidence: 99%

Poly(ADP-ribose) polymerase-1 and its ambiguous role in cellular life and death

Castedo¹,

Lafarge²,

Kroemer³

2023

CST

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“…The synergism between ICB and PARP inhibitors in women with OC has been reported in vitro and in vivo preclinical models and it is under evaluation in several clinical trials, both in chemo-naive and pretreated patients. 37 The ENGOT-Ov44/FIRST trial (NCT03602859) is a phase III study which randomizes treatment-naïve OC patients to receive SoC chemotherapy (± bevacizumab) followed by niraparib maintenance or the combination of SoC chemotherapy (± bevacizumab) plus dostarlimab followed by maintenance with niraparib plus dostarlimab. The original design of the study included also a third arm of SoC chemotherapy followed by placebo maintenance; this arm was later discontinued in light of the outcome of the PRIMA and PAOLA-1 trials, 38 , 39 which established maintenance treatment with PARP inhibitors alone or in combination with antiangiogenic agent bevacizumab as the standard of care for high-grade OC.…”

Section: Key Ongoing Clinical Trialsmentioning

confidence: 99%

Dostarlimab: From preclinical investigation to drug approval and future directions

Cicala

Musacchio

Scambia

et al. 2023

Human Vaccines & Immunotherapeutics

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Immune checkpoint blockers (ICB) act by reverting the immunosuppressive phenotype of cancer cells, thus allowing host immune system to generate an immune response to the tumor. One of the key mechanisms targeted by ICB is the PD-1/PD-L1 axis, which lies onto the interaction between the programmed-cell death protein 1 and its ligand, overexpressed in several tumor types. This interaction leads to the inhibition of T-cell proliferation and their apoptosis and exhaustion. Anti-PD-1/PD-L1 monoclonal antibodies are now the mainstay of treatment for several advanced stage tumors. Dostarlimab is a novel IgG4 anti-PD-1 antibody which has yielded remarkable results in mismatch-repair deficient endometrial cancer and locally advanced rectal cancer. This product review will illustrate the preclinical development of dostarlimab and its pharmacological characteristics, the clinical trials published so far and the ongoing clinical investigations.

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“…In particular, the combination of PARPi and the PD-L1/PD-1 blockade has been tested in several clinical trials. 54 Table 1 shows the ongoing phase 3 clinical trials with immunotherapy for ovarian cancer (Table 1). [55][56][57][58] PARPi can be effective in combination therapy because it may produce neoantigens via a DNA repair mechanism and cause tumor cells to be recognized by T cells.…”

Section: Future Perspectives In Immunotherapies For Ovarian Cancermentioning

confidence: 99%

“…The addition of chemotherapies or molecular targeted therapies with the PD‐L1/PD‐1 blockade has been also evaluated. In particular, the combination of PARPi and the PD‐L1/PD‐1 blockade has been tested in several clinical trials 54 . Table 1 shows the ongoing phase 3 clinical trials with immunotherapy for ovarian cancer (Table 1).…”

Section: Future Perspectives In Immunotherapies For Ovarian Cancermentioning

confidence: 99%

Mini‐review: Immunology in ovarian cancer

Taki

2023

J of Obstet and Gynaecol

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Immunotherapy for ovarian cancer has been studied for many years and programmed cell death protein 1 ligand/programmed cell death protein 1 (PD‐L1/PD‐1) blockade has been attempted in several clinical trials; however, the expected therapeutic effect has not been achieved. In contrast, the PD‐L1/PD‐1 blockade has been clinically applied to endometrial and cervical cancers, and a certain therapeutic effect has been observed. In endometrial cancer, promising outcomes have been achieved with a combination of an anti‐PD‐1 antibody and lenvatinib, regardless of the number of regimens, even in cases of recurrence after platinum administration. Therefore, immunotherapy is expected to have a therapeutic effect on ovarian cancer regardless of platinum resistance. In this review, considering immunotherapy for ovarian cancer, we discuss the immune mechanisms that exist in ovarian cancer and the immunotherapeutic strategies that should be developed.

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Combining PARP inhibition and immune checkpoint blockade in ovarian cancer patients: a new perspective on the horizon?

Cited by 18 publications

References 73 publications

Poly(ADP-ribose) polymerase-1 and its ambiguous role in cellular life and death

Poly(ADP-ribose) polymerase-1 and its ambiguous role in cellular life and death

Dostarlimab: From preclinical investigation to drug approval and future directions

Mini‐review: Immunology in ovarian cancer

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