Mechanisms of HIF-driven immunosuppression in tumour microenvironment

Bandopadhyay, Shinjini; Patranabis, Somi

doi:10.1186/s43046-023-00186-z

Journal of the Egyptian National Cancer Institute

Table 2 Combination therapies tested in recent years

From: Mechanisms of HIF-driven immunosuppression in tumour microenvironment

Drug	Mechanism of action	Combined with immunotherapy	Tumour	Cell line/model	Therapeutic results	Overall clinical outcome	Current investigations	Ref.
TH-302	Hypoxia-activated prodrug	Immune checkpoint blockade of PD-1 and CTLA-4	Prostate cancer	Transgenic adenocarcinoma of the mouse prostate-derived (TRAMP-derived) TRAMP-C2 cell line Male C57BL/6, Pb-Cre4, Ptenpc − / − Smad4pc − / − mice models	CD8 + T cells with increased granzyme B production, proliferation of CD44, and production of effector cytokines	Cured more than 80% of tumours TRAMP-C2 mice models Survival of mice with aggressive prostate adenocarcinoma significantly extended	Ongoing clinical trial (NCT03098160) being conducted to evaluate efficacy of TH-302 in combination with CTLA-4 blocker ipilimumab in melanoma, pancreatic, and prostate tumours	[103, 104]
PX-478	HIF-1α mRNA and protein translation inhibitor	Dendritic cell (DC) tumour vaccine	Breast cancer	4T1 cell line Female BALB/c mice bearing 4T1 tumours	Decreased hypoxia-induced HIF-1α protein levels and reduction in HIF-activated VEGF	Complete tumour regression in 50% mice with significant prolongation of survival	Ongoing studies on refining efficacy of DC vaccination especially in combination with HIF targeting drugs	[105] [106]
PX-478	HIF-1α mRNA and protein translation inhibitor	Checkpoint blockade of PD-1	Non-small cell lung cancer (NSLC)	Human A549 and H1299 cell lines Female C57BL/6 mice	Inhibition of EMT-associated HIF-1α/LOXL2 axis, increased T-cell infiltration	Better sensitization of tumour to immune checkpoint blockade, marked delay in tumour growth, and prolonged survival	More clinical trials required to further verify the efficacy and safety of the HIF-1α inhibitor with anti-PD-1 blockade	[107]
Acriflavine	Inhibitor of HIF-1α/HIF-1β dimerization	Both TRP-2 peptide vaccine and anti-PD-1 blocking antibody	Melanoma and breast cancer	B16-F10 and 4T1 cell lines C57BL/6 and immunodeficient NOD SCID gamma mice	Inhibited melanoma tumour growth, increased infiltration of NK and CD8 + T cells into TME via release of CCL2 and CCL5 chemokines	Improved response to standard immunotherapy, better survival	Considerations for triple combination therapy	[108]
IDF-11774	HIF-1α inhibitor	Checkpoint blockade of PD-1	Prostate cancer	Murine prostate cell-derived xenograft (CDX) model set up in nude mice and BALB/c mice	Reduced MSDC and M2 macrophage population, increased T-cell infiltration	Augmented antitumor efficacy of PD-1 blockade, reduction in tumour volume	No data yet	[109]

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