Immune Checkpoint Inhibitors: The New Breakout Stars in Cancer Treatm | Page 10

Table 5 . Combination of immune checkpoint inhibitors and vaccines

IMMUNE CHECKPOINT INHIBITOR

PHASE I NCT02529072 Nivolumab / Opdivo Dendritic cell ( DC ) vaccine Recurrent malignant glioma , astrocytoma , glioblastoma

NCT01386502 CT-011 ( anti-PD-1 ) p53 : 264-272 peptide ( vaccine , targeted to p53 gene )

Breast cancer , colon cancer , pancreatic cancer , sarcoma , ovarian cancer

PHASE I / II NCT02439450 Nivolumab / Opdivo Viagenpumatucel-L Metastatic NSCLC , treated at least once

NCT02466568 GM . CD40L Lung cancer

NCT02499835 Pembrolizumab / MK-3475 / Keytruda pTVG-HP Plasmid DNA Vaccine

Hormone-resistant prostate cancer

NCT02515227 6MHP ( peptide vaccine ) Melanoma , after failed treatment with ipilimumab

PHASE II NCT01096602 CT-011 ( anti-PD-1 ) DC Acute myelogenous leukemia ( AML ) vaccine

AML after remission with chemotherapy

NCT01067287 DC fusion vaccine Multiple myeloma after autologous stem cell transplantation ( ASCT )

NCT01441765

DC / Renal cell carcinoma ( RCC ) fusion vaccine

Renal cell carcinoma

PHASE III NCT00094653 MDX-010 ( anti-CTLA-4 ) MDX-1379 ( gp100 ) Metastatic melanoma

deployed in sequence or simultaneously to enhance their effects . There are a number of opportunities to enhance the immunity against tumors using dual or triple immune checkpoint blockade ( Table 4 ), based on the expression of multiple inhibitory ligands by tumors and of multiple inhibitory receptors by TILs . In addition , new anti-PD-1s continue to be studied , such as PDR001 , which is currently undergoing a first-in-human Phase I / II study ( NCT02404441 ) for melanoma , NSCLC , TNBC , and other solid tumors .

For example , CTLA-4 and PD-1 are both inhibitory receptors , 21 but appear to play complementary roles in regulating adaptive immunity . PD-1 limits T cell activity during an inflammatory response to infection and to limit autoimmunity ; activated T cells induce PD-1 expression , which is broader than that of CTLA- 4 . CTLA-4 is expressed solely on T cells and plays a role in the regulation of T cell activation amplitude during the early stages . Therefore , combined treatment involves dual immune checkpoint inhibition that results in increased anti-tumor activity .

Ipilimumab and nivolumab was the first immune checkpoint inhibitor combination approved by the FDA ( October 2015 ), for the treatment of BRAF V600 wild-type unresectable or metastatic melanoma . The approval was based on the results of the CheckMate-069 study , in which the ORR with the combined treatment was 60 %, compared with 11 % with ipilimumab alone for patients with previously untreated unresectable or metastatic melanoma . 22 In addition , 16 patients ( 22 %) in the combination group experienced a complete response , compared with no patients in the ipilimumab-monotherapy group .

Previous studies had also demonstrated positive results with the same combination ( ipilimumab and nivolumab ), with a 40 % ORR in patients with advanced melanoma . 23 In the CheckMate-032 study for small cell lung cancer ( SCLC ), the combination of nivolumab and ipilimumab resulted in an ORR of 31.1 %, with a 2.2 % complete response rate , compared with an ORR of 16.4 % with nivolumab only . 21

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