Page 122 - Read Online

Page 777 Wong et al. Cancer Drug Resist 2023;6:768-87 https://dx.doi.org/10.20517/cdr.2023.58

CD8+ T cells, thereby triggering an immune response towards the tumour. Indeed, studies have shown that
increasing neoantigen formation helps to improve response to ICIs [81-83] .

Antibody-drug conjugates
Similar to the rationale for combining ICIs with chemotherapy which was discussed earlier, antibody-drug
conjugates (ADCs) also increase tumour neoantigen formation via immunogenic cell death . An ADC
[84]
consists of an antigen-specific monoclonal antibody bound to a cytotoxic payload via a molecular linker.
The binding of an ADC via its antigen-binding portion induces its internalisation via endocytosis. Once
inside the tumour cell, cleavage of its linker through proteolysis results in the release of the cytotoxic
payload. This allows for target-dependent activation and selective cytotoxicity . Of note, two ADCs,
[85]
namely trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan, have received FDA approvals for the
treatment of specific breast cancer subtypes. T-DXd is approved for unresectable or metastatic HER2-
positive breast cancer based on the results of DESTINY-Breast 03, confirming significant PFS benefit (HR
[86]
0.28; P < 0.0001) , as well as for unresectable or metastatic HER2-low breast cancer based on DESTINY-
Breast 04 showing both promising PFS (HR 0.50; P < 0.001) and OS (HR 0.64; P = 0.001) benefit .
[87]
Sacituzumab govitecan, on the other hand, has been approved both for unresectable or metastatic TNBC as
well as hormone-positive, HER2-negative breast cancer based on the ASCENT and TROPiCS-02 trials,
respectively, both confirming PFS and OS benefit [88,89] .

Preclinical data have suggested that the combination of ADCs with ICIs may improve the efficacy of ICIs
via increasing neoantigen formation and presentation, as well as by activating DCs and increasing the
expression of PD-L1 . There are currently several ongoing trials evaluating the combination of different
[85]
ADCs with ICIs. In the earlier described BEGONIA study, two ADCs, T-DXd and datopotamab deruxtecan
(Dato-DXd), are being studied in arms 6 and 7 of the trial, respectively. Preliminary data for both arms were
promising; ORR with the addition of T-DXd was 66.7% and 74% with the addition of Dato-DXd . Other
[90]
[91]
ongoing trials in this space are summarised in Table 2.
Poly(ADP-ribose) polymerase inhibitors
Poly(ADP-ribose) polymerase (PARP) inhibitors increase DNA damage, leading to more TSAs and also
[92]
increased MHC-I expression, thereby causing increased antigen presentation . The increase in DNA
damage associated with breast cancer patients who harbour the BRCA1/2 mutation occurs via a process
[93]
known as synthetic lethality . The use of PARP inhibitors blocks the repair of single-stranded DNA breaks
via base excision repair. This allows single-stranded breaks to accumulate, leading to the generation of
double-stranded breaks (DSBs). These DSBs can usually be restored by either the high-fidelity homologous
repair pathway or the error-prone non-homologous end-joining method. As BRCA1/2 mutant breast cancer
patients already have existing defects in homologous repair, they are unable to effectively repair DNA
damage, resulting in the generation of TSAs. In addition to increasing antigen presentation, PARP
inhibitors have also been shown in preclinical studies to alter the TME by activating intra-tumoural
dendritic cells and increasing CD8+ T cell infiltration via the STING (stimulator of interferon genes)
pathway . It also enhances the upregulation of PD-L1 expression by reducing the PARylation of STAT3 .
[95]
[94]
The latter two mechanisms help to overcome tumour extrinsic mechanisms of resistance to immunotherapy
that will be expounded upon later.

Consequently, there have been several studies evaluating the combination of PARPi together with ICIs. The
TOPACIO/KEYNOTE-162 trial studied the efficacy of niraparib together with pembrolizumab in 55
[96]
patients with metastatic TNBC. In the subgroup of patients with BRCA1/2 mutations, the ORR was 47% and
mPFS 8.3 months. In contrast, patients who were non-BRCA1/2 mutants had an ORR of 11% and mPFS of