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Table 3. Ongoing clinical trials investigating CART cells immunotherapy
Study drug Combination Study phase Treatment setting Sponsor Clinicaltrials.gov
identifier
CART-meso None I Second line University of Pennsylvania NCT03323944
None N/A Second line Shenzhen BinDeBio NCT03638193
None I/II Second line National Cancer Institute NCT01583686
CART-Nectin4 None I Second line The Sixth Affiliated Hospital of NCT03932565
Wenzhou Medical University
CART-EpCAM None I/II Any First Affiliated Hospital of NCT03013712
Chengdu Medical College
CART-CD70 Cyclophosphamide, I/II Second line National Cancer Institute (NCI) NCT02830724
Fludarabine, Aldesleukin
CART-CLD18 Cylophosphamide, N/A Any Kang YU, First Affiliated Hospital NCT03302403
Fludarabine of Wenzhou Medical University
CART-TnMUC1 Cylophosphamide, I Second line Tmunity Therapeutics NCT04025216
Fludarabine
CART-PSCA Rimiducid I/II Second line Bellicum Pharmaceuticals NCT02744287

activate the T cell when an antigen is bound. These cells are expanded ex-vivo and re-infused into patients.
In a phase I trial in which mesothelin-specific CAR-T cells were given to 6 patients with chemotherapy-
refractory metastatic PDAC, 2 patients had stable disease with PFS of 3.8 and 5.4 months. Additionally,
one patient had 69.2% decrease in metabolic activity on PET (positron emission tomography) scan with
complete reduction in FDG (F-2-fluoro-2-deoxy-D-glucose) uptake in all liver lesions at 1 month but no
[85]
effect was seen on primary PDAC . Only small numbers of patients have been treated with adoptive T-cell
therapy and there have been variable results in metastatic sites versus primary tumor. There are currently
various other preclinical and phase I/II trials with CAR T cells targeting various tumor antigens such as
Nectin4/FAP, EpCAM, CD70, CLD18, TnMUC1, PSCA (NCT03932565, NCT03013712, NCT02830724,
NCT03302403, NCT04025216, NCT02744287) [Table 3].

Although clinical data suggests that vaccines and CAR T-cell therapy can elicit anti-tumor T cell responses
in PDAC with suggestion of clinical benefit, no clinically meaningful responses have been reported with
CAR T-cell treatment of PDAC. These approaches have the potential to target the PDAC specifically;
however, the tumor fighting cells may not be able to reach their target due to the desmoplasia and
immunosuppressive tumor microenvironment. There may be also be other barriers to effective anti-tumor
immune therapy. Further studies are needed to better understand and target these barriers.

OTHER TARGETED AGENTS
There are also strategies using agents that target DNA repair, pathway inhibitors, metabolism and
extracellular matrix. Some of the notable ones are discussed below [Table 4].

PARP inhibitors
Poly (ADP-ribose) polymerase (PARP) enzymes repair single stranded DNA breaks and play crucial roles
in DNA damage repair (DDR). PARP inhibitors are small molecules that trap PARP enzymes on DNA and
prevent the process of DDR. Cancer cells with deficient in DNA repair via homologous recombination due
[86]
to mutations in BRCA 1/2 are very sensitive to PARP inhibitors . The presence of PARP inhibitors lead to
death of BRCA 1/2 mutated cancer cells due to a markedly reduced capacity for DDR. The first randomized,
phase III trial, POLO found that maintenance therapy with a PARP inhibitor, Olaparib, significantly
prolonged the progression of disease in advanced PDAC with germline BRCA gene mutations compared
to placebo (PFS 7.3 months vs. 3.8 months) . Currently, there are several clinical trials at varying phases
[87]
studying the efficacy of different PARP inhibitors in advanced PDAC.