Cancer cells, 3D illustration

Pancreatic Cancer & Advanced Solid Tumors – LSTA1

What is pancreatic ductal adenocarcinoma (PDAC)?

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid malignancies with poor prognosis and a rising incidence. Late detection and a particularly aggressive biology are the major challenges which determine therapeutic failure. PDAC is the most prevalent neoplastic disease of the pancreas accounting for more than 90% of all pancreatic malignancies [1]. A large portion of patients are diagnosed with locally advanced or metastatic disease at the time of presentation which severely limits the number of patients who can undergo surgical resection, currently the only treatment option available that offers a chance for cure. In metastasis, cancer cells break away from where they first formed (primary cancer), travel through the blood or lymph system, and form new tumors (metastatic tumors) in other parts of the body. The metastatic tumor is often the same type of cancer as the primary tumor. Recent therapeutic advanced for patients with advanced pancreatic cancer have extended overall survival, but prognosis remains grim. 

To date, PDAC is the fourth most frequent cause of cancer-related deaths worldwide, and the twelfth most common cancer in the world [2,3]. The incidence of PDAC is expected to rise further in the future, and projections indicate a more than two-fold increase in the number of cases within the next ten years, both in terms of new diagnoses as well as in terms of PDAC-related deaths in the U.S. and in European countries [4,5]. The five-year survival of pancreatic cancer from time of diagnosis is around 11.5% in the U.S. and the five-year survival rate for patients diagnosed with metastatic disease is only 3% [6]. In 2022, it is estimated that there will be 62,210 new cases of pancreatic cancer and an estimated 49,830 people will die of this disease in the US alone [6].

Treatment options for pancreatic cancer

Different types of treatments are available for patients with pancreatic cancer. Some treatments are standard, whereas others are being tested in clinical trials. The efficacy of PDAC treatments is largely determined by the stage of disease at the time of diagnosis. Surgical resection followed by adjuvant chemotherapy is the only potentially curative therapy available, yet only 10-20% of PDAC patients present with resectable PDAC stages, while the residual 80-90% show locally advanced, non-resectable stages or – in the majority – distant metastases [7,8]. Systemic chemotherapy is commonly employed as first-line treatment in patients with non-resectable or borderline-resectable tumors. This chemotherapy encompasses nucleoside analogues, including gemcitabine and capecitabine, or the pyrimidine analogue 5-fluorouracil in monotherapy settings or in combination with other treatment modalities, such as radiotherapy [8,9,10]. Despite these treatments, the drug resistance to PDAC still leads to extremely poor outcomes. The dense fibrous stroma surrounding the tumor mass, together with the abnormal vasculature network and the immune-suppressive microenvironment typical of this cancer type, are among the causes of this drug resistance. The tumor microenvironment in PDAC is composed of a stiff extracellular matrix (“ECM”) creating a physical barrier against penetration [11]. The ECM is a non-cellular meshwork of crosslinked macromolecules that form a dense desmoplastic stroma around tumor cells. This complex meshwork, together with the formation of new collapsed and leaky blood vessels, creates a tumor microenvironment in favor of tumor growth and invasiveness. Thus, the presence of the ECM, poor/tortuous vascularity of the tumor, and high interstitial tumor pressure may cause, in some cases, only a small fraction of an administered drug to cross this dense desmoplastic stroma barrier and reach the tumor.

Immunotherapies, such as “checkpoint inhibitors,” work by enhancing the ability of patients’ immune systems to identify and fight their cancer. Other types of immunotherapies, such as adoptive cell therapies, introduce additional immune cells with the intent to fight patients’ cancer. While this emerging class of immunotherapies may benefit patients combatting several types of cancer, the only approved immunotherapy for pancreatic cancer is limited to the 1-3% of patients with high microsatellite instability. In pancreatic and many other advanced solid tumor cancers, the tumor’s dense stroma may reduce immune cells’ ability to penetrate the tumor. Additionally, the tumor immuno-microenvironment in pancreatic as well as other solid tumor cancers is dominated by immunosuppressive cell types, such as T regulatory cells (Tregs), which further inhibit the ability of the patients’ immune system or immunotherapies to fight cancer.

Our Approach: LSTA1 for the treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC) 

LSTA1, formerly known as CEND-1, the lead product candidate from the CendR Platform™, has the potential to be combined with a myriad of chemo and immunotherapeutic agents that could become an integral part of a revised standard-of-care therapy for many difficult to treat cancers. The Lancet Gastroenterology and Hepatology published encouraging data from the Phase 1 study of LSTA1 in combination with gemcitabine and nab-paclitaxel for the treatment of first-line, metastatic pancreatic ductal adenocarcinoma (mPDAC). The publication details the results of an open-label, multi-center, Phase 1 trial conducted in 31 patients in the safety population and 29 patients in the efficacy population. The objectives of the study were to determine the safety, tolerability, pharmacokinetics, and preliminary efficacy of LSTA1 in combination with gemcitabine and nab-paclitaxel in patients with mPDAC. 

LSTA1 for the Treatment of Advanced Solid Tumors

Similar to mPDAC, many advanced solid tumors are characterized by a dense ECM, creating a physical barrier against penetration, which limits anti-cancer drug delivery. In addition, many solid tumors have failed standard-of-care therapies and are not well addressed by available immunotherapies due to the tumor microenvironment being dominated by immuno-suppressive cell types that impair immune response. 

Lisata aims to address the key limitations that enable effective treatment of advanced solid tumors by targeting and penetrating the dense desmoplastic stroma and by reducing the immuno-suppressive tumor microenvironment that limits immune response to cancer. In addition, Lisata is focused on depleting certain immuno-suppressive cell types, such as Tregs and increasing the number of cancer-fighting immune cells.

What is LSTA1?

LSTA1, formerly known as CEND-1, is an investigational drug that is intended to modify the tumor microenvironment. It targets tumor vasculature by its affinity for alpha-v integrins that are selectively expressed in tumors, but not healthy tissue vasculature. LSTA1 is a cyclic peptide that, once bound to these integrins, is cleaved by proteases expressed in tumors. Once cleaved to a linear peptide fragment, called a CendR fragment, CendR binds to a second receptor, called neuropilin-1, to activate a novel uptake pathway that allows anticancer drugs to penetrate solid tumors more efficiently and selectively. The ability of LSTA1 to modify the tumor microenvironment to enhance delivery and efficacy of co-administered drugs has been demonstrated in models of a range of solid tumors. LSTA1 has also been shown to decrease the percentage of immunosuppressive Tregs and to increase the percentage of cancer fighting CD8+ T cells selectively within the tumor in animal models of pancreatic cancer. 

Investigational Clinical Trials of LSTA1 in Metastatic Pancreatic Ductal Adenocarcinoma & Advanced Solid Tumors

IndicationPre ClinicalPhase 1Phase 2Phase 3

Indication: First-Line Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC)

Gemcitabine/nab-paclitaxel with LSTA1 or placebo (Australia/New Zealand)
First-Line Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC)
Gemcitabine/nab-paclitaxel with LSTA1 or placebo (Australia/New Zealand)
Phase 2
Gemcitabine/nab-paclitaxel + LSTA1 (China)
Gemcitabine/nab-paclitaxel + LSTA1 (China)
Phase 1
Gemcitabine/nab-paclitaxel/LSTA1± atezolizumab (Multi-national) 
Gemcitabine/nab-paclitaxel/LSTA1± atezolizumab (Multi-national) 
Phase 1

Indication: Pancreatic, Colon, and Appendiceal Cancers

LSTA1 + FOLFIRINOX + panitumumab* (U.S.)
Pancreatic, Colon, and Appendiceal Cancers
LSTA1 + FOLFIRINOX + panitumumab* (U.S.)
Phase 1

Indication: Various Solid Tumors

SoC with LSTA1 or placebo (U.S.)
Various Solid Tumors
SoC with LSTA1 or placebo (U.S.)
Phase 2

References

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