Immunotherapy‐based combination strategies for advanced urothelial cancer: A long quest

Abstract

LAY SUMMARY: • Despite longer survival with immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)/programmed cell deathligand 1 (PD-L1), metastatic urothelial carcinoma remains lethal. There is an unmet need to further improve the efficacy of these agents. • In their phase 2 trial, Zhang et al. evaluated the combination of pembrolizumab (a PD-1 inhibitor) plus acalabrutinib (a novel agent inhibiting an enzyme considered relevant to immunotherapy resistance) based on strong rationale but did not demonstrate clinical benefit compared with pembrolizumab alone. • Future trials that examine such promising rational combinations may be able to evaluate selected patients based on validated biomarkers to optimize benefit in an endless pursuit of personalizing therapies. Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have significantly altered the treatment landscape for patients with locally advanced / unresectable or metastatic urothelial cancer (aUC). However, response rates with these agents remain modest (approximately 13%-29%), 1 and therefore there is much interest in identifying additional agents that can meaningfully potentiate the effect of PD-(L)1 axis inhibitors. 2 Many clinical trials have been designed to date to investigate combination therapies with agents hypothesized to have relevant immune-modulating activity to improve outcomes further without causing intolerable toxicity. 2 Against this backdrop, the Randomized Phase 2 Trial of Acalabrutinib and Pembrolizumab Immunotherapy Dual Checkpoint Inhibition in Platinum-Resistant Metastatic Urothelial Carcinoma (RAPID CHECK, ACE-ST-005, Keynote 143, NCT02351739) trial was designed and executed. In this phase 2 trial by Zhang et al, 3 published in this issue of Cancer, patients with aUC were randomized to treatment with pembrolizumab alone or in combination with the oral inhibitor of Bruton tyrosine kinase (BTK), acalabrutinib. BTK is expressed on myeloid-derived suppressor cells (MDSCs), 4 which suppress T-cell activity and support an immunosuppressive tumor microenvironment. This is thought to be a mechanism of resistance to immune checkpoint blockade. 5-9 BTK also plays a role in the activation of other inflammatory cells (mast cells, myeloid cells, etc) in the tumor microenvironment to facilitate tumor growth and proliferation. 10 Based on the above compelling data, Zhang et al 3 hypothesized that concurrent PD-1 and BTK inhibition would have an additive or synergistic effect in patients with aUC. Unfortunately, despite this robust rationale, the trial did not demonstrate benefit with the use of this combination. The overall response rate (ORR) with combination therapy was not significantly different from that with pembrolizumab monotherapy (20.0% vs 25.7%, respectively) and the combination resulted in more significant adverse events (AEs) compared with pembrolizumab alone (grade 3/4 AEs [according to the National Cancer Institute Common Terminology Criteria for...

Immune checkpoint inhibitors in advanced upper and lower tract urothelial carcinoma: a comparison of outcomes

“…radiotherapy), and (v) antibody‐drug conjugates (e.g. enfortumab vedotin, sacituzumab govitecan), among others [42–44]. As with many combination regimens, we should carefully consider whether potential improvement of outcomes is the result of drug independence (which may address tumour heterogeneity among patients) rather than true additivity or synergism (which may address intra‐tumour heterogeneity in an individual patient) [45].…”

Reinforcing the Combinational Immuno-Oncotherapy of Switching “Cold” Tumor to “Hot” by Responsive Penetrating Nanogels

“…As shown in the 1 H NMR spectrum of DMAEP (Figure S3B), 1 H NMR (400 MHz, CDCl 3 -d, δ): and 5.58−6.12 (4H, H-2, CH 2 C), respectively. The purity of DMAEP was 93.01%, measured by HPLC (Figure S4).…”

“…The synthetic routes of the different molecules are shown in Figures S1A−S3A. The 1 H NMR spectrum of HAm is presented in Figure S1B, 1 As shown in the 1 H NMR spectrum of HCD-A (Figure S2B), 1 H NMR (400 MHz, D 2 O-d 2 , δ): 1.02 (3H, H-i), 3.37− 4.16 (9H, H-b, c, d, e, f, g, h), 4.95 (1H, H-a), and 5.92−6.34 (3H, H-1, CHCH 2 ), respectively. The peaks of 5.92−6.34 ppm (3H, H-1, CHCH 2 ) were accounted for the vinyl group, and the DS was 45.20%.…”

“…Immunotherapy has emerged as a new type of therapeutic method for cancer, which activates our immune system to eliminate tumors. , However, the overall response rate of the most popular immune checkpoint blockade therapy in clinic, programmed cell death receptor-1/programmed death 1 ligands (PD-1/PD-L1) antibodies, is only around 20–40%. − This is mainly due to the contained infiltration and suppressed activation of immune cells in the suppressive tumor microenvironment (TME), which can be considered as “cold” tumors. , Therefore, to develop innovative strategies for turning the “cold” tumor into “hot” to improve the activation and immersion of tumor infiltration lymphocyte and to further eliminate the tumor immunosuppressive condition has become a crucial issue for effective immuno-oncotherapy. , In such a direction, the synergetic approaches by regulating the key processes of anti-tumor immune responses, for example, the maturation of antigen-presenting cells (APCs), activation and infiltration of effector T cells in tumors, and the relief of the T cell suppression condition, may essentially reverse the suppressive TME in “cold” tumors and achieve a more powerful anti-tumor capacity. − …”

“…Immunotherapy has emerged as a new type of therapeutic method for cancer, which activates our immune system to eliminate tumors. 1,2 However, the overall response rate of the most popular immune checkpoint blockade therapy in clinic, programmed cell death receptor-1/programmed death 1 ligands (PD-1/PD-L1) antibodies, is only around 20− 40%. 3−6 This is mainly due to the contained infiltration and suppressed activation of immune cells in the suppressive tumor microenvironment (TME), which can be considered as "cold" tumors.…”