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Extracellular Matrix And Its Therapeutic Potential For Cancer Treatment
Pancreatic cancer is the seventh leading cause of cancer-related mortality in both sexes across the globe. It is associated with extremely poor prognosis and remains a critical burden worldwide due to its low survival rates. Histologically, pancreatic ductal adenocarcinoma (PDAC) accounts for 80% of all pancreatic cancers; the majority of which are diagnosed at advanced stages, which makes them ineligible for curative surgery. Conventional chemotherapy provides a five-year overall survival rate of less than 8% forcing scientists and clinicians to search for better treatment strategies. Recent discoveries in cancer immunology have resulted in the incorporation of immunotherapeutic strategies for cancer treatment. Particularly, immune-checkpoint inhibitors, adoptive cell therapies and cancer vaccines have already shifted guidelines for some malignancies, although their efficacy in PDAC has yet to be elucidated. In this review, we summarize the existing clinical data on immunotherapy clinical outcomes in patients with advanced or metastatic PDAC.
Pancreatic cancer is the seventh leading cause of cancer-related mortality in both sexes across the globe [1]. It remains a critical burden worldwide due to its low survival rates and extremely aggressive nature [2]. A total of 95% of pancreatic malignancies arise from exocrine parts (ductal epithelium, acinar cells and connective tissue), and another 5% develop from endocrine parenchyma [3]. Histologically, pancreatic ductal adenocarcinoma (PDAC) accounts for 80% of all pancreatic cancers [4], and the majority of cases are diagnosed at advanced stages (Figure 1) [5]. Localized cases can be treated with surgery, however, the five-year overall survival (OS) rate does not exceed 25% [6]. Unfortunately, there are no curative strategies for advanced stages, and palliative chemoradiotherapy reaches a five-year OS rate of less than 8% [7]. Chemotherapeutic choices of treatment include either modified FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) [8], gemcitabine monotherapy or gemcitabine in combination with nab-paclitaxel [9].
Recent discoveries in cancer immunology resulted in the incorporation of immunotherapeutic strategies for the treatment of various solid and hematologic malignancies [10]. Multiple clinical trials showed the higher efficacy of immune-checkpoint inhibitors (ICIs) for melanoma, lung cancer, renal cell carcinoma, colorectal cancer and hepatocellular carcinoma [11, 12, 13, 14, 15]. Adoptive chimeric antigen receptor (CAR) T-cell therapy is another immunotherapeutic tool being established as effective for hematologic malignancies, particularly relapsed/refractory B cell lymphoma [16] or mantle-cell lymphoma [17]. Unfortunately, early-phase clinical trials have shown limited responses to immunotherapy in patients with PDAC [18, 19]. Nevertheless, immunotherapy is still deemed the most likely way to improve prognosis for patients with advanced PDAC (aPDAC) in the near future [20]. In this review, we provide an overview of the clinical outcomes of immunotherapy in patients with advanced and/or metastatic PDAC.
Intravital Imaging Technology Guides Fak Mediated Priming In Pancreatic Cancer Precision Medicine According To Merlin Status
Figure 1. Overview of pancreatic ductal adenocarcinoma (PDAC): tumor microenvironment and classification. (A) Stages of PDAC’s progression, according to the AJCC’s 8th edition [21]. (B) Morphological differences between normal (left) and malignant (right) pancreatic tissue. (C) TNM classification of PDAC.
ICIs have heralded a new era in clinical oncology [22]. ICIs are monoclonal antibodies that target immune checkpoints (e.g., cytotoxic T-lymphocyte antigen-associated protein 4 [CTLA-4], programmed cell death-1 [PD-1], programmed cell death ligand 1 [PD-L1]) on T-, cancer and antigen-presenting cells (Figure 2) [23]. The inhibition of immune checkpoints results in proper stimulation of T-cell receptor (TCR) signaling, differentiation of cytotoxic T cells and further destruction of malignant cells [24].
In 2011, Ipilimumab (IPI), an anti-CTLA-4 monoclonal antibody, became the first ICI to be approved by the US Food and Drug Administration (FDA) [25]. Though it shifted treatment guidelines for melanoma [26], trials elucidating IPI in patients with aPDAC did not show any promising results. In particular, a single-arm phase 2 trial established that IPI (3 mg/kg) monotherapy in aPDAC patients (74% [n = 20] pre-treated with gemcitabine-based regimens) failed to show any durable response [27]. Furthermore, 11.1% (n = 3) of patients developed severe (≥grade 3) immune-related adverse events (irAEs) [27].
Stage 1 Pancreatic Cancer
A dose-escalation phase 1b trial (NCT01473940) presented that IPI in combination with gemcitabine reached an objective response rate (ORR) of 14% (n = 3) [28]. Moreover, the median progression-free survival (PFS) was 2.78 months (95% CI, 1.61 to 4.83) with a median OS of 6.9 months (95% CI, 2.63 to 9.57) [28]. A total of 19% (n = 4) developed irAEs of grade 3 or higher [28]. Overall, a combinatorial therapy of gemcitabine 1000 mg/m
+ IPI 3 mg/kg was considered safe; however, the efficacy outcomes did not exceed the results of gemcitabine monotherapy, and thus further exploration was halted.
Another CTLA-4 inhibitor tremelimumab was studied in a phase 2 basket trial (NCT02527434) [29]. A pooled analysis of patients with aPDAC (pre-treated with gemcitabine) revealed that 90% (n = 18) had disease progression [29]. The median OS reached 4 months (95% CI: 2.8 to 5.4) with 70% (n = 14) experiencing irAEs of grade 3 and higher. Thus, second-line tremelimumab monotherapy failed to show superior efficacy in patients with aPDAC [29].
Types Of Pancreatic Cancer
Similar to IPI, a dose-escalation phase 1b study revealed that the combination of tremelimumab with gemcitabine showed better effectiveness than monotherapy [30]. In particular, the median OS reached 7.4 months (95% CI, 5.8 to 9.4) with 6% (n = 2) reaching PR [30] and only 3% (n = 1) developing serious irAEs [30].
A phase 2 trial (NCT02558894) established that a combination of tremelimumab 75 mg + durvalumab 1500 mg (anti-PD-L1 inhibitor) reached an ORR of 3.1% (n = 1) with 22% (n = 7) developing irAEs of grade 3 and higher [31]. The trial failed to reach the pre-designed ORR threshold of 10%, and further exploration was stopped.
Finally, recent results of a randomized phase 2 trial (NCT02879318) comparing arm A (gemcitabine + nab-paclitaxel) to arm B (gemcitabine + nab-paclitaxel + durvalumab + tremelimumab) established no significant difference in survival [32]. In particular, the median OS was 8.8 months (95% CI: 7.2 to 11.2) and 9.8 months (95% CI: 8.3 to 12.2) in arms A and B, respectively (Hazard Ratio [HR]: 0.94, p = 0.72) [32]. The median PFS was 5.4 months (95% CI: 3.6 to 6.6) and 5.5 months (95% CI: 3.8 to 5.7) in arms A and B, respectively (HR: 0.98, p = 0.91) [33]. Serious adverse events were reported in 44.8% (n = 26) and in 68.9% (n = 82) of patients in arms A and B, respectively [33]. Thus, combinatorial immunotherapy failed to show a significantly higher efficacy in aPDAC patients than the current standard of care (SoC).
New Targets In The Fight Against Pancreatic Cancer｜tokyo Medical And Dental University, National University Corporation
To sum up, the existing results do not show encouraging outcomes for CTLA-4 inhibitors in patients with aPDAC. Strikingly, even the combination of the PD-L1 inhibitor durvalumab + CTLA-4 inhibitor tremelimumab is not significantly better than SoC chemotherapy. This data emphasizes the need for further studies on novel combinatorial approaches able to overcome the unique immunosuppressive and fibrotic morphological features of PDAC that potentially play a major role in the inhibition of existing ICI-based regimens. Moreover, further trials should be designed for the head-to-head comparison of a single ICI or a combination of CTLA-4 + PD-1 inhibitors to the current SoC or SoC + ICI.
Pembrolizumab (PEMBRO) and nivolumab (NIVO) are humanized monoclonal antibodies (mAbs) inhibiting the PD-1 inhibitory checkpoint [34]. They have been granted FDA approval for the treatment of melanoma, lung cancer and aPDAC with MSI-H status [19].
A single-arm phase 2 trial (NCT01876511) reported that cohort C (non-colorectal cancer patients [n = 7 out of whom n = 4 with PDAC] with a mismatch repair deficiency [dMMR] or a high microsatellite instability [MSI-H]) treated with PEMBRO as a ≥2 line of therapy reached an ORR of 71% with a median PFS of 5.4 months [35]. The authors concluded that PEMBRO alone showed a durable clinical efficacy in the MSI-H patients from cohort C [36]. Later reports from the NCT01876511 trial also observed durable response in the cohort of patients (n = 86) with PDAC (ORR 53% [95% CI: 42% to 64%]; 21% of patients reached complete response [CR]) [37]. A recent report from the multicenter KEYNOTE-158 trial reported that out of n = 22 patients only n = 4 (18.2%) had
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