Methods of treating neuroendocrine tumors that overexpress somatostatin receptors

Abstract

A method for treating neuroendocrine tumors that overexpress somatostatin receptors is provided. [Solution] The present invention relates to a method for treating cancers that overexpress somatostatin receptors. More specifically, the present invention provides a combination therapy in which a combination of peptide receptor radionuclide therapy (PRRT) and immuno-oncology therapy (IO therapy) is administered for the treatment of neuroendocrine tumors. In a specific embodiment, the PRRT is [177]lutetium-DOTA[O]-Tyr[3]-octreotate, and the IO therapy comprises administering an inhibitor that inhibits the PD-1 / PD-L1 and CTLA-4 pathways.

Description

[Technical Field]

[0001] Related Applications [Not applicable]

[0002] Technical Field The present invention relates to methods for treating cancers that overexpress somatostatin receptors. More specifically, the present invention provides a combination therapy in which a combination of peptide receptor radionuclide therapy (PRRT) and immuno-oncology therapy (IO therapy) is administered to treat neuroendocrine tumors. [Background technology]

[0003] Neuroendocrine neoplasias occur in a variety of organ sites and tissue types. Neuroendocrine tumors (NETs) are tumors arising from cells of the endocrine (hormonal) and nervous systems. They include a group of tumors with a range of morphological, functional, and behavioral characteristics. These tumors generally grow slowly. However, they have the potential to spread, primarily to the liver, and when they do, they can be life-threatening and difficult to treat with current modalities.

[0004] NETs are rare, heterogeneous tumors that originate from dispersed neuroendocrine cells distributed throughout the body. The term "neuroendocrine" refers to the ability of these cells to synthesize, store, and secrete neurohormones, neurotransmitters, or neuromodulators produced by both the endocrine and nervous systems.

[0005] Most patients with NETs do not experience symptoms, and their tumors are discovered only during unrelated surgery or examinations. Functional NETs, ​​which produce certain hormones and other chemicals, often cause patients to experience symptoms, but the nonspecific nature of these symptoms can lead to delayed or even misdiagnosis. By the time a patient with a NET is correctly diagnosed, the cancer has usually metastasized, with local or distant metastases observed in approximately 50% of cases. Once metastatic, NETs cannot be effectively treated by surgery alone and are generally incurable.

[0006] Thus, there is a significant need for therapies for NETs, ​​but there are only a limited number of options currently available for the treatment of advanced NETs.

[0007] The cornerstone of NET treatment is the use of somatostatin analogs (SSAs), such as Sandostatin (Novartis) or Somatuline® (Ipsen). Traditionally, SSAs have been used for symptomatic treatment, yet some antitumor activity has been confirmed. Chemotherapy and targeted therapy have only been registered for pancreatic NETs (pNETs), while the use of SSAs for gastrointestinal (GI) or pulmonary NETs has only limited approval. As a result, many patients exhaust all available treatment options, especially in the advanced disease setting, which represents a high unmet medical need for systemic treatment of metastatic NETs.

[0008] At the palliative level, SSAs are used to control certain clinical syndromes associated with metastatic carcinoid tumors, including severe diarrhea, flushing episodes, and cardiac disease (collectively referred to as carcinoid syndrome).

[0009] Most NETs overexpress somatostatin receptors (SSTRs). These protein G-coupled receptors, which sense extracellular molecules and activate intracellular events in response to the hormone somatostatin, are expressed in human cells. This short-lasting endogenous hormone is a key regulator of the endocrine system, and somatostatin analogs that mimic its activity have proven highly effective in inhibiting the activity of growth hormone, glucagon, and insulin, thereby controlling carcinoid syndrome-related symptoms. Growth hormone, glucagon, and insulin are also frequently produced by carcinoid tumors.

[0010] However, symptomatic treatment of carcinoid syndrome is separate from treating the metastatic NETs themselves. Based on its partial antiproliferative effect, Ipsen's Somatuline® Depot® (lanreotide) was approved by the FDA in December 2014 for the treatment of adult patients with unresectable, well- or moderately differentiated, locally advanced, or metastatic NETs (GEPNETs) of the gastroenteropancreatic tract. Everolimus (Afinitor®, an oral inhibitor of the mammalian target of rapamycin (mTOR)) has been approved in the US for the treatment of advanced neuroendocrine tumors of pancreatic origin and well-differentiated, nonfunctioning, unresectable, locally advanced, or metastatic NETs of gastrointestinal (GI) or pulmonary origin (11-month PFS observed in a phase 3 trial). To date, these are the only "antineoplastic" therapies approved for midgut tumors. However, when tumors become resistant or unresponsive to treatment, usually approximately 6 to 18 months after initiating treatment, 1、2、3 There are no other therapies approved for intervention in GI and pulmonary NETs, ​​and therefore these tumors are untreatable by currently available therapies.

[0011] Chemotherapeutic agents and some targeted therapies have become the standard of care for pNETs, ​​but response rates vary depending on tumor aggressiveness and are estimated to be between approximately 30% and 50%. Two targeted therapies have been approved for the treatment of progressive, nonfunctioning pNETs, ​​but the survival benefit is limited.

[0012] As discussed above in

[0010] , the first of these targeted therapies is the use of Afinitor® (everolimus), an inhibitor of the mammalian target of rapamycin (mTOR), however, treatment with Afinitor® can result in severe skin and gastrointestinal disorders, kidney and liver toxicity, and bone marrow damage.

[0013] The only other treatment is the use of Sutent® (sunitinib), a multitargeted receptor tyrosine kinase inhibitor, or RTK, approved by the FDA and EMA in 2011 for the treatment of unresectable or metastatic well-differentiated pNETs with disease progression in adults based on a PFS of 11.4 months observed in a phase 3 trial. Again, this is a less-than-ideal intervention because treatment with Sutent® can result in severe side effects, such as renal failure, cardiac failure, gastrointestinal disorders, bleeding, and hematologic disorders (e.g., neutropenia, thrombocytopenia, and anemia), which are among its most common adverse drug reactions.

[0014] Thus, traditional chemotherapy has little role in the treatment of well-differentiated NETs because most of these tumors are slow-growing and difficult to treat. Rigorous assessment of chemotherapy efficacy in the literature is difficult due to the majority of retrospective studies on heterogeneous patient series, where toxicity is associated and responses are short-lived and sporadic, especially in "midgut carcinoids." Many schemes, including single or multiple agents, have been attempted.

[0015] Streptozotocin-based treatments in pancreatic tumors have produced significant objective responses. However, none of the schemes used in "midgut carcinoids" have shown any activity in the treatment of NETs. Some good early responses have been reported in small groups with the combination of temozolomide + capecitabine. 4 Again, these early data reveal that currently available therapies for NETs are inadequate and that there is a long-felt and urgent need for additional robust therapies that can produce substantial therapeutic outcomes. Summary of the Invention [Means for solving the problem]

[0016] The present invention, described in more detail below, provides a combination therapy approach to effectively treat NETs.

[0017] The present invention relates to a method of treating a patient afflicted with a tumor that overexpresses somatostatin receptors, comprising administering to said patient a combination of peptide receptor radionuclide therapy (PRRT) and IO therapy.

[0018] In a specific embodiment, the PRRT is lutetium-DOTA[O]-Tyr[3]-octreotate.

[0019] In a specific embodiment, the IO therapy comprises administering an inhibitor that inhibits the PD-1 / PD-L1 and CTLA-4 pathway. In other embodiments, the PD-1 / PD-L1 and CTLA-4 pathway inhibitor is an antibody that targets the PD-1 / PD-L1 axis or the CTLA-4 / B7 receptor complex. In yet a further embodiment, the PD-1 / PD-L1 pathway inhibitor is a combination of inhibitors that target both PD-1 and PD-L1.

[0020] In certain embodiments, the PD-1 / PD-L1 or CTLA-4 / B7 pathway is inhibited by nivolumab, MK-3475, MPDL3280A, MED I 4736, ipilimumab, and tremelimumab.

[0021] The present invention is particularly defined by embodiments in which the cancer is a neuroendocrine tumor. More specifically, the treatment includes one or more of the following methods: inhibiting neuroendocrine tumor growth, inhibiting neuroendocrine tumor cell proliferation, inhibiting neuroendocrine tumor metastasis, reducing the tumorigenicity of neuroendocrine tumor cells, and reducing the frequency of cancer stem cells or tumor-initiating cells within a neuroendocrine tumor.

[0022] Any neuroendocrine tumor that expresses or overexpresses somatostatin receptor can be treated by the method of the present invention.Exemplary tumors of this type include but are not limited to: gastroenteropancreatic neuroendocrine tumor, carcinoid tumor, pheochromocytoma, paraganglioma, medullary thyroid carcinoma, pulmonary neuroendocrine tumor, thymic neuroendocrine tumor, carcinoid tumor or pancreatic neuroendocrine tumor, pituitary adenoma, adrenal gland tumor, Merkel cell carcinoma, breast cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, head and neck tumor, urothelial carcinoma (bladder), renal cell carcinoma, hepatocellular carcinoma, GIST, neuroblastoma, bile duct tumor, cervical tumor, Ewing's sarcoma, osteosarcoma, SCLC, prostate cancer, melanoma, meningioma, glioma, medulloblastoma hemangioblastoma, supratentorial primitive, neuroectodermal tumor and nasal neuroblastoma.

[0023] In particular examples, the neuroendocrine tumor is selected from the group consisting of a functional carcinoid tumor, an insulinoma, a gastrinoma, a vasoactive intestinal peptide (VIP) tumor, a glucagonoma, a serotoninoma, a histaminoma, an ACTH tumor, a pheocromocytoma, and a somatostatinoma.

[0024] Neuroendocrine tumors treated by the present invention can be defined by grade, The tumor may be a low-grade, intermediate-grade, or high-grade neuroendocrine tumor. In a specific embodiment, the tumor is a functioning neuroendocrine tumor. Alternatively, the neuroendocrine tumor is a non-functioning neuroendocrine tumor.

[0025] In particularly preferred embodiments, the cancer is small cell lung cancer. In other preferred embodiments, the cancer is advanced midgut neuroendocrine tumor. In some embodiments, the present invention provides a therapy for neuroendocrine tumors that are unresponsive to Sandostatin (Novartis) or Somatuline® (Ipsen). In other embodiments, the neuroendocrine tumor is unresponsive or has a poor response to inhibitors of the PD-1 / PD-L1 pathway. The present invention provides, for example, the following items. (Item 1) A method of treating a patient having a cancer that overexpresses a somatostatin receptor, comprising administering to the patient a combination of peptide receptor radionuclide therapy (PRRT) and immuno-oncology therapy, wherein the combined effect of the PRRT and the immuno-oncology therapy results in a therapeutic effect against the cancer. (Item 2) 1. A method of treating a patient having a cancer that overexpresses somatostatin receptors, comprising administering to the patient a combination of peptide receptor radionuclide therapy (PRRT) and an inhibitor that inhibits the PD-1 / PD-L1 / CTLA-4 pathway, wherein the combined effect of the inhibitors of the PRRT and PD-1 / PD-L1 pathway results in a therapeutic effect against the cancer. (Item 3) The method of item 1, wherein the PRRT is lutetium-DOTA[O]-Tyr[3]-octreotate. (Item 4) 2. The method of item 1, wherein the inhibitor of the PD-1 / PD-L1 / CTLA-4 pathway is an antibody that targets PD-L1. (Item 5) 2. The method of claim 1, wherein the inhibitor of the PD-1 / PD-L1 pathway is an antibody that targets PD-1. (Item 6) The inhibitor of the PD-1 / PD-L1 pathway is selected from the group consisting of nivolumab, MK-3475, MPDL3280A, and MED I 4736, ipilimumab, and tremelimumab. (Item 7) Item 10. The method of item 1, wherein the cancer is a neuroendocrine tumor. (Item 8) 7. The method of claim 6, wherein the treatment comprises one or more of the following methods: inhibiting neuroendocrine tumor growth, inhibiting neuroendocrine tumor cell proliferation, inhibiting neuroendocrine tumor metastasis, inducing neuroendocrine tumor cell differentiation, reducing the tumorigenicity of neuroendocrine tumor cells, and reducing the frequency of cancer stem cells or tumor-initiating cells within neuroendocrine tumors. (Item 9) 7. The method of item 6, wherein the neuroendocrine tumor is selected from the group consisting of gastroenteropancreatic neuroendocrine tumor, carcinoid tumor, pheochromocytoma, paraganglioma, medullary thyroid carcinoma, pulmonary neuroendocrine tumor, thymic neuroendocrine tumor, carcinoid tumor or pancreatic neuroendocrine tumor, pituitary adenoma, adrenal gland tumor, Merkel cell carcinoma, breast cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, head and neck tumor, urothelial carcinoma (bladder), renal cell carcinoma, hepatocellular carcinoma, GIST, neuroblastoma, bile duct tumor, cervical tumor, Ewing's sarcoma, osteosarcoma, SCLC, prostate cancer, melanoma, meningioma, glioma, medulloblastoma hemangioblastoma, supratentorial primitive, neuroectodermal tumor, and nasal neuroblastoma. (Item 10) 7. The method of claim 6, wherein the neuroendocrine tumor is selected from the group consisting of a functional carcinoid tumor, an insulinoma, a gastrinoma, a vasoactive intestinal peptide (VIP) tumor, a glucagonoma, a serotoninoma, a histamine tumor, an ACTH tumor, a pheochromocytoma, and a somatostatinoma. (Item 11) 7. The method of item 6, wherein the neuroendocrine tumor is a low-grade, intermediate-grade, or high-grade neuroendocrine tumor. (Item 12) Item 10. The method of item 1, wherein the cancer is small cell lung cancer. (Item 13) 2. The method of claim 1, wherein the cancer is an advanced midgut neuroendocrine tumor. (Item 14) 13. The method of claim 12, wherein the cancer is not responsive to Sandostatin (Novartis) or Somatuline® (Ipsen). (Item 15) 2. The method of item 1, wherein the cancer is unresponsive or has a low response to inhibitors of the PD-1 / PD-L1 pathway. (Item 16) 7. The method of item 6, wherein the neuroendocrine tumor is a functional neuroendocrine tumor. (Item 17) 7. The method of item 6, wherein the neuroendocrine tumor is a non-functioning neuroendocrine tumor. DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention provides methods for inhibiting neuroendocrine tumor growth, inhibiting neuroendocrine tumor cell proliferation, treating or stabilizing neuroendocrine cancer, inhibiting neuroendocrine tumor metastasis, reducing the tumorigenicity of neuroendocrine tumor cells, and reducing the frequency of cancer stem cells or tumor-initiating cells in neuroendocrine tumors. More specifically, the methods provided herein involve administering a peptide receptor radionuclide in combination with immuno-oncology therapy. In some embodiments, peptide receptor radionuclide therapy (PRRT) is a therapy that uses a radiolabeled SSA peptide with high affinity for the somatostatin receptor (sstr), carrying a radioisotope such as Lu-177 within its overall structure. In the present invention, PRRT is combined with a PD-1 and / or PD-L1 / CDLA-4 inhibitor.

[0027] LutaThera:

[0028] SSA is a synthetic version of the endogenous hormone somatostatin, which has a longer half-life than wild-type endogenous somatostatin hormone. In a specific embodiment, the preferred molecule used in PRRT is Lutathera (lutetium-DOTA[O]-Tyr[3]-octreotate), which is a ready-to-inject solution of Lu-177-labeled SSA.

[0029] Lutathera consists of three components. The first component is SSA octreotate, a peptide that targets NET cells. The second component is DOTA, a compound that can combine with metals (such as Lu-177) in a complex through a ring structure. The third component is Lu-177, a radioisotope.

[0030] Lutathera treats certain NETs by selectively binding to the SSTR2 receptor, the receptor most commonly expressed on these types of tumors. Lutathera then destroys the NET cells in a targeted manner by delivering a localized release of high-energy electrons. Lutathera also emits gamma rays, which may also be useful as a disease management tool, because this type of emission can be captured by a SPECT camera and therefore used to determine drug distribution and pharmacokinetics, and also for dose estimation.

[0031] Overall, given the current limited options and efficacy for the treatment of NETs, ​​and specifically the lack of treatment for advanced midgut NETs, ​​Lutathera could fill a significant medical need by potentially improving patient outcomes in the treatment of advanced midgut NETs and other somatostatin receptor-positive tumors.

[0032] Lutathera is the first-ever PRRT (peptide receptor radionuclide therapy) radiopharmaceutical being tested in a Phase 3 clinical trial for the treatment of inoperable, advanced, well-differentiated, SSTR2-positive, midgut NETs.

[0033] The current Phase 3 trial is a multicenter, randomized, active-controlled, parallel-group study evaluating the efficacy and safety of Lutathera (using a total cumulative administered radioactivity of 29.6 GBq) compared with Sandostatin® LAR 60 mg.

[0034] Immuno-oncology therapy

[0035] Immuno-oncology therapy (or IO therapy) is an emerging field of cancer treatment that harnesses the body's own immune system to fight disease. The goal of IO therapy is to restore the immune system's ability to eliminate cancer cells, either by directly activating the immune system or by inhibiting tumor-mediated suppression mechanisms.

[0036] The immune system relies on multiple checkpoints or "immunological brakes" to avoid overactivation of the immune system on healthy cells. 5、6 Downregulating the immune system by preventing T cell activation reduces autoimmunity and promotes self-tolerance. Tumor cells often exploit these checkpoints to escape detection by the immune system. CTLA-4 and PD-1 are checkpoints that have been investigated as targets for cancer therapy. 5、6 .

[0037] Programmed cell death protein 1, also known as PD-1, is a cell surface receptor expressed on T cells. PD-1 binds to PD-L1, which is expressed on a variety of cells in the body, including many tumor cells, and this inhibits T cell function, which contributes to the tumor's ability to evade the immune system. 5、6 .

[0038] Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4; also known as CD152) is expressed on the surface of T cells, where it primarily suppresses these early steps of activation by inducing inhibitory downstream T cell receptor (TCR) signaling and counteracting the activity of the T cell costimulatory receptor, CD28. 19、20 CTLA-4 is thought to outcompete CD28 for B7 ligands (CD80 and CD86) on the surface of antigen-presenting cells by binding with higher affinity and avidity. 21 In preclinical studies, blocking CTLA-4 resulted in a 1.5- to 2-fold increase in T cell proliferation and a 6-fold increase in interleukin-2 production. 22 .

[0039] The physiological role of CTLA-4 is not only to suppress effector T cells (Teff) but also to enhance the function of immunosuppressive CD4+FoxP3+ regulatory T cells (Treg). Treg-specific CTLA-4 deficiency has been shown to reduce the suppressive capacity of Tregs in cell culture and result in upregulation of CD80 and CD86 expression on dendritic cells (DCs). showed 23 CTLA-4 blockade has been shown to promote T cell activation and, in preclinical models, to deplete intratumoral Tregs in a process that depends on the presence of Fcγ receptor-expressing macrophages in the tumor microenvironment. 24、25 .

[0040] On March 25, 2011, the U.S. Food and Drug Administration approved ipilimumab injection (YERVOY, Bristol-Myers Squibb Company) for the treatment of unresectable or metastatic melanoma. Approval was based on a randomized (3:1:1), double-blind, double-dummy clinical trial (MDX010-20) in patients with unresectable or metastatic melanoma who had received at least one prior systemic treatment for melanoma. Overall survival (OS) was the primary endpoint of the trial. Progression-free survival and best overall response rate were also assessed.

[0041] Ipilimumab received marketing authorization in the European Union (EU) on July 13, 2011, and is currently approved for the indication "treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy." In accordance with Article 16 of Commission Regulation (EC) No. 1234 / 2008, Bristol-Myers Squibb Pharma EEIG submitted an application for a variation, including an indication extension, to the European Medicines Agency on August 2, 2012. In October 2013, the MAH proposed an indication extension for Yervoy for the treatment of previously untreated adult patients with advanced (unresectable or metastatic) melanoma.

[0042] Ipilimumab has been evaluated in combination with RT in patients with metastatic CRPC and melanoma. Promising activity with manageable tolerability was observed in a phase I / II trial in patients with CRPC that had progressed after antiandrogen therapy. 26 Results from a phase III trial showed that adding ipilimumab to RT in post-docetaxel CRPC did not significantly improve OS. Subgroup analysis did suggest a benefit for patients with less advanced disease. 27 Analysis of clinical data from 21 patients with advanced melanoma who received RT after ipilimumab during the Italian Expanded Access Program showed that RT after ipilimumab treatment could further enhance its efficacy. 28 A local response to RT was detected in 13 patients (62%), while 8 patients (38%) did not experience any local regression. The median OS for all 21 patients was 13 months (range 6-26). Eleven of the 13 patients with a local response (85%) demonstrated an abscopal response, suggesting that a local response to RT may be predictive of abscopal response and outcome. The median OS for patients with and without abscopal response was 22.4 months (range 2.5-50.3) and 8.3 months (range 7.6-9.0), respectively. Currently, more than 15 clinical trials are underway evaluating ipilimumab plus RT alone.

[0043] Both PD-1 and PD-L1 inhibitors target the interaction between PD-1 and PD-L1, which dampens immune responses. Inhibiting checkpoints such as PD-1 or PDL-1 "releases the brakes" on the immune system and can enhance antitumor T cell responses. This class of therapy has demonstrated efficacy in cancer. Compared with other previously tested immunotherapies, PD-1 / PD-L1 inhibitors, when used as monotherapy, appear to shrink tumors in a much higher percentage of patients across a broader range of tumor types and with a lower rate of high-grade toxicities, primarily immune-mediated side effects. Compared with standard therapies, including chemotherapy and "targeted" therapies, immunotherapies, including PD-1 / PD-L1 inhibitors, also appear to result in longer duration of response.

[0044] Nivolumab (Opdivo, Bristol-Myers Squibb), which targets the PD-1 receptor, was approved in Japan in July 2014 for the treatment of metastatic melanoma (second-line). It was approved by the US FDA in December 2014. In April 2015, it received a positive opinion from the EMA for approval as monotherapy for metastatic melanoma. It is currently being investigated in non-small cell lung cancer (NSCLC, squamous cell third-line) and Hodgkin lymphoma (third-line).

[0045] Some tumor types, including prostate, colorectal, and pancreatic cancer, have shown little response to anti-PD-1 / PD-L1 monotherapy in early clinical trials. For such diseases, and for non-responders within the group of more immune-responsive tumor types, combination therapy may be useful in eliciting an immune response. Clinical trials have not yet been proposed for neuroendocrine tumors.

[0046] PD-L1 and PD-1 protein expression was analyzed in 94 clinical cases of small cell carcinoma 7None of the small cell carcinomas showed PD-L1 protein expression in tumor cells. PD-L1 and PD-1 expression were observed in the stroma. Using immunohistochemistry, 18.5% of cases showed PD-L1 expression in tumor-infiltrating macrophages, and 48% showed PD-1-positive lymphocytes. RNA-seq showed moderate PD-L1 gene expression in 37.2% of cases. PD-L1 correlated with macrophage and T-cell markers. A second PD-1 ligand, PD-L2, was expressed in 27.9% of cases and showed a similar correlation. Thus, the PD-1 / PD-L1 pathway appears to be activated in a proportion of small cell carcinomas. Other experiences from Charite Hospital (Berlin) and Badberka Central Hospital (Germany) have also been reported. 8 These results suggest a higher presence of CD3-positive lymphocytes and PD-L1 expression in poorly differentiated NETs compared with well-differentiated ones. Therefore, the authors concluded that PD-1 / PD-L1 may be promising targets for immunotherapy, especially in poorly differentiated NETs.

[0047] Nevertheless, patients with PD-L1 / PD-L2 expression may respond to anti-PD-1 treatment. However, tumor PD-L1 expression is not a perfect predictor of response to PD-1 / PD-L1 inhibitors when used as monotherapy. Indeed, PD-L1-negative tumors may still respond at a lower percentage, while PD-L1-positive tumors are more likely to respond, although not all of them will.

[0048] Small cell lung cancer and extrapulmonary small cell carcinoma are the most aggressive types of neuroendocrine carcinoma (G3), also called poorly differentiated neuroendocrine carcinoma (PDNEC). There has been no study of the PD-1 / PD-L1 pathway in more indolent forms of neuroendocrine tumors, such as G1 and G2 (also called well- or moderately differentiated tumors), originating from other organs.

[0049] Antonia et al. [AdRef.11] reported preliminary data at ASCO 2014 on 49 patients treated with the combination of nivolumab and ipilimumab. Patients received either nivolumab 1 mg / kg plus ipilimumab 3 mg / kg or nivolumab 3 mg / kg plus ipilimumab 1 mg / kg for four cycles, followed by nivolumab alone. Treatment-related, grade 3-4 AEs occurred in 49% of patients, and 35% of patients discontinued the study drug due to treatment-related AEs. The most common grade 3-4 treatment-related AEs included diarrhea (n=5, 10%), elevated ALT (n=4, 8%), elevated AST (n=4, 8%), colitis (n=4, 8%), elevated lipase (n=4, 8%), fatigue (n=3, 6%), and interstitial pneumonitis (n=3, 6%). The discontinuation rate due to drug-related AEs was highest in the nivolumab 1 mg / kg / ipilimumab 3 mg / kg non-squamous arm, with most discontinuations occurring during the concurrent phase of treatment. Response rates ranged from 11% to 33%, with some patients experiencing prolonged duration of response.

[0050] Antonia et al. [AdRef.11] reported that the combination of tremelimumab and MEDI4736 The results were reported at ASCO 2015. Of 102 patients treated with MEDI4736 plus tremelimumab in the dose-escalation phase, 40% had grade 3 or higher treatment-related AEs, with the most common treatment-related grade 3-4 events being colitis (n=9, 9%), diarrhea (n=8, 8%), interstitial pneumonitis (n=4, 4%), increased AST (n=4, 4%), and increased ALT (n=3, 3%). The observed response rate was 27% across all cohorts, with 41% experiencing disease control (CR, PR, and SD for at least 16 weeks). 28、29 .

[0051] Recent studies suggest that radiation therapy can be applied as a powerful adjuvant for immunotherapy and may actually contribute to the conversion of irradiated tumors into in situ vaccines, resulting in specific immunity against tumor cells. 9、10 .

[0052] However, the clinical observation that best demonstrates the induction of antitumor immunity by external beam radiation therapy is the abscopal effect, which refers to the regression of unirradiated lesions in patients treated with concurrent radiation therapy. Although this has been reported in multiple tumor types over the years, the abscopal effect is infrequent. 9、 These rare events reflect existing barriers to successful immunization with radiation therapy.

[0053] The optimal irradiation regimen used to exploit the proimmunogenic effect of irradiation has yet to be determined. The synergistic effects of external beam radiation and checkpoint inhibitor therapy have been tested in various studies. However, fractionation and dose appear to play a major role in inducing the synergistic effects of irradiation and checkpoint inhibitor treatment. 11 .

[0054] Even when fractionated, the effect of external beam radiation therapy in increasing antitumor immunity is temporary.

[0055] This drawback could surprisingly be overcome by using peptide receptor radionuclide therapy.

[0056] Thus, the present invention relates to a novel combination of PRRT and IO that can synergistically reduce cancer cell proliferation without increasing the toxicity profile compared to the individual drugs.

[0057] In addition to its ability to disrupt the tumor cell cycle through the delivery of ionizing radiation, PRRT can induce antitumor immune responses. For example, treatment with Lutathera PRRT in a human xenograft tumor model of NETs was observed to increase CD86+ APC infiltration and CD86 expression on these cells. 12 .

[0058] Due to their receptor-mediated mechanism of action, PRRT agents allow for continuous, stable internal radiation therapy, resulting in increased, consistent, and durable antigen exposure.

[0059] In this context, the immunogenicity-promoting effects of radiation therapy can be enhanced by using PRRT to correct the immunosuppressive network that is in place once the tumor is established. Modern IO agents, such as anti-PD-1 / PD-L1 / CTLA-4, are gradually taking on the challenge of breaking established tolerance to cancer and restoring effective tumor-specific immune responses. The proposed combination uses a novel mechanism: metabolic pathways (overexpression of somatostatin receptors by tumors) to create tumor lesions that release tumor antigens and induce cell death via internal irradiation of cells that make themselves visible to the immune system. Immunotherapies, such as immune checkpoint blockade (e.g., inhibition of the PD-1 / PD-L1 / CTLA-4 pathway), should improve immune antitumor T-cell responses and enhance the effects of radiation in a synergistic and unexpected manner. be.

[0060] The use of PRRTs in conjunction with SSA agonists may be advantageous for durable responses based on their recognized stable internalization throughout therapy while sparing healthy tissue. For this purpose, the use of specific PRRTs with the property of being internalized by tumor cells may be preferable (e.g., Lutathera).

[0061] Lymphotoxicity is commonly observed after PRRT 13、14 This toxicity is the main factor that prevents physicians and oncologists from advocating the combination of PRRT and IO. For example, Denoyer et al. (2015) noted that Lu-DOTATATE is toxic to peripheral blood lymphocytes. It is generally accepted that both T and B lymphocytes play a crucial role in the immune response to cancer (Linnebacher et al.). However, the present inventors also demonstrated that the toxicity of Lutathera is more specific to B-lymphocytes. 16This finding is important because T lymphocytes are the most abundant tumor infiltrates and therefore most implicated in fighting cancer.

[0062] Lymphopenia after PRRT may reduce immunological responses, and Lu177 16 Rather, it is more severe with the Y90 radionuclide.

[0063] Milan 31 Bodei et al. (Bodei L et al., 2014) from the group of Pharmacists, presented a retrospective analysis of post-PRRT toxicity in 807 patients treated with 177Lu-based PRRT, 90Y-based PRRT, or the two compounds combined between 1997 and 2013. Severe hematological toxicity grades 3-4 were observed in 14.1% of cases treated with 90Y PRRT and 3.1% of cases treated with 177Lu, indicating a more favorable hematological safety profile of PRRT with Lu-DOTATATE (Lutathera) compared with Y90.

[0064] Finally, the toxicity profiles of the two treatments (PRRT and IO) are different and therefore they are not expected to cause a significant increase in side effects for patients.

[0065] For example, Lutathera administration can result in hematologic toxicity that primarily affects B cells but not T cells, and therefore Lutathera should not affect the immune response of T cell-based anti-PD1 / PDL1 / CTLA-4 treatments. Considering the above, it is anticipated that combining Lutathera with inhibitors that block the PD-1 / PD-L1 / CTLA-4 pathway will provide an effective new treatment for traditionally difficult-to-treat NETs.

[0066] This combined effect should occur in any cancer that overexpresses somatostatin receptors. This combination should extend the efficacy of PRRT (e.g., Lutathera) for grade I-II NETs (the efficacy for which Lutathera is considered appropriate) and enable significant therapeutic effects in cancers that have not shown significant responses to Lutathera in phase I-II clinical trials or proof-of-concept studies, such as grade III NETs. Small cell lung cancer and extrapulmonary small cell carcinoma, the most aggressive types of neuroendocrine cancer, could benefit from this combination with unexpected results.

[0067] In support of this theory, several studies using other types of agents of PRRT, mainly in combination with chemotherapy, have shown very good results.

[0068] Co-expression of sstr2 and PD-1 / PD-L1 and / or PD-L2 receptors on some neuroendocrine tumor tissues overexpressing sstr2 was demonstrated by immunohistochemistry. Human tumor tissue samples from small cell lung cancer and colorectal cancer (both neuroendocrine) were used for this evaluation. The relationship between sstr2 expression and CTLA-4 has not been widely reported.

[0069] Formalin-fixed, paraffin-embedded (FFPE) tissue sections (5-6 μm thick) were used. The sections were dried and deparaffinized. Immunohistochemistry (IHC) staining was performed using anti-PD-1 (1:100 dilution), anti-PD-L1 (1:50 dilution), and anti-SSTR2 (1:100 dilution) primary antibodies from Thermo Fisher Scientific. Anti-rabbit and anti-mouse secondary antibodies from the ImmunoCruz LSAB Staining System were used. Following the standard IHC staining procedure, the incubation time for the primary antibody was 1 hour 45 minutes. For the secondary antibody, the incubation time was 30 minutes. At the end of the IHC procedure, the tissues were dehydrated and images were captured using an Olympus BX60 with a Leica DFC420C and a Leica Acquired using LAS software.

[0070] Preliminary results of IHC staining indicate expression of PD-1 and sstr2 receptors in both tissue types. PD-L1 appears to be expressed to a lower extent in the analyzed tissue samples, but further analysis is ongoing.

[0071] Additional immunohistochemical analyses and mRNA assays on tissue samples from other sstr2-expressing tumors are underway to further support the principles of this invention. Furthermore, additional exploratory preclinical studies are planned to assess the efficacy of combination therapy with 177Lu-DOTATATE and anti-PD1 (or anti-PDL-1 and CTLA-4) antibodies in appropriate rat pancreatic models of neuroendocrine tumors.

[0072] Treatment method

[0073] The present invention provides a method for treating neuroendocrine tumors. Neuroendocrine tumors (NETs) are tumors that arise from cells of the endocrine (hormonal) and nervous systems. Neuroendocrine tumors (NETs) include a group of tumors with a wide range of morphological, functional, and behavioral characteristics. These tumors generally grow slowly but have the potential to spread, primarily to the liver, and when they do spread, they can be life-threatening and difficult to treat with current modalities.

[0074] Neuroendocrine tumors have traditionally been classified by their site of origin. In certain embodiments, the NET is selected from the group consisting of pancreatic neuroendocrine tumors (pNETs) and carcinoid tumors of the lung, stomach, duodenum, jejunum, ileum, colon, and rectum. In further embodiments, the NET is selected from the group consisting of neuroendocrine tumors of the ovary, thymus, thyroid medulla, adrenal gland (e.g., pheochromocytoma), and paraganglia (paraganglioma). In certain embodiments, the NET treated by the methods described herein is small cell lung cancer (SCLC). In certain alternative embodiments, the NET is non-small cell lung cancer. In certain embodiments, the NET is a pancreatic neuroendocrine tumor (PET) or a carcinoid tumor. In certain embodiments, the NET is non-small cell lung cancer, pancreatic cancer, or thyroid cancer.

[0075] Neuroendocrine tumors are also classified by grade and differentiation. See, e.g., Phan et al., Pancreas, 39(6):784-798 (2012). 15 In certain embodiments, the neuroendocrine tumor is a well-differentiated, low-grade tumor. In certain embodiments, the neuroendocrine tumor is a moderately differentiated, medium-grade tumor. In certain embodiments, the neuroendocrine tumor is a poorly differentiated, high-grade tumor. In one embodiment, the low-grade tumor is A tumor is characterized by fewer than 2 mitoses per 10 HPF (high power fields) and no necrosis. In one embodiment, a medium-grade tumor is characterized by 2-10 mitoses or foci of necrosis per 10 HPF (high power fields). In one embodiment, a high-grade tumor is characterized by more than 10 mitoses per 10 HPF (high power fields).

[0076] In other embodiments, neuroendocrine tumors can be divided into grade 1-2 neuroendocrine tumors (or well-differentiated endocrine tumors or carcinomas (WDET / WDEC)), grade 3 neuroendocrine carcinomas or poorly differentiated endocrine carcinomas (carinomas) / small cell carcinomas (PDEC), mixed adeno-neuroendocrine carcinomas (MANEC), and hyperplastic and preneoplastic lesions based on the WHO classification system 2000 and 2010. According to the ENETS / WHO / AJCC classification system, tumors G1 are those with a Ki67 index ≦2% or MI (mitotic count) <2, tumors G2 are those with a Ki67 index within 3-20% or MI = 2-20, and tumors G3 are those with a Ki67 index ≧20% or MI >20.

[0077] Neuroendocrine tumors are also classified as functional and non-functional NETs. NETs are considered functional when specific clinical syndromes are induced due to the excessive production of hormones by tumor cells. Examples of functional NETs include but are not limited to carcinoid tumors, which can cause carcinoid syndrome, and functional pNETs, ​​such as islet cell adenomas, gastrinomas, vasoactive intestinal peptide (VIP) tumors, glucagonomas, and somatostatinomas.

[0078] Non-functioning NETs are not associated with clinical syndromes resulting from the overproduction of hormones by tumor cells, but may still cause symptoms related to the presence of the tumor or its metastases (e.g., abdominal pain or bloating). In certain embodiments, the neuroendocrine tumor is a functioning NET. In certain embodiments, the neuroendocrine tumor is a non-functioning NET. In certain embodiments, the neuroendocrine tumor is selected from the group consisting of a functioning carcinoid tumor, an islet cell adenoma, a gastrinoma, a vasoactive intestinal peptide (VIP) tumor, a glucagonoma, a serotoninoma, a histamine tumor, an ACTH tumor, a pheochromocytoma, and a somatostatinoma. In certain embodiments, the neuroendocrine tumor is an NSCLC.

[0079] In certain embodiments, the neuroendocrine tumor is a primary tumor. In alternative embodiments, the neuroendocrine tumor is a metastatic tumor. In certain embodiments, the neuroendocrine tumor has not spread outside the wall of the primary organ. In certain embodiments, the neuroendocrine tumor has spread through the wall of the primary organ and into surrounding tissues, such as fat, muscle, or lymph nodes. In certain embodiments, the neuroendocrine tumor has spread to tissues or organs distant from the primary organ, such as the liver, bone, or lung.

[0080] In specific embodiments, it is contemplated that the methods of the present invention will be particularly useful in treating neuroendocrine cancers or tumors that are refractory to treatment. As a non-limiting example, the cancer or tumor may be chemoresistant (i.e., resistant to one or more forms of chemotherapy). In certain embodiments, the cancer or tumor is resistant to treatment with a somatostatin analog. In certain embodiments, the cancer or tumor is resistant to treatment with a kinase inhibitor. In yet other embodiments, the cancer or tumor is resistant to treatment with an inhibitor of the PD-1 / PD-L1 / CTLA-4 pathway.

[0081] In certain embodiments, the neuroendocrine cancer or tumor has metastasized to the liver. By way of non-limiting example, the neuroendocrine cancer or tumor is a carcinoid or pancreatic neuroendocrine tumor that has metastasized to the liver.

[0082] In one aspect, the present invention provides the use of PPRT in combination with IO therapy in the treatment of neuroendocrine tumors.This treatment combination is useful for inhibiting neuroendocrine tumor growth, reducing neuroendocrine tumor volume, and / or reducing the tumorigenicity of neuroendocrine tumors.The method of use can be in vitro, ex vivo, or in vivo.In certain embodiments, the PPRT is Lutathera.PRRT is a type of targeted radionuclide therapy, i.e., a form of treatment that delivers therapeutic doses of radiation to malignant tumors, for example, by administering radiolabeled molecules designed to seek out certain cells.In certain embodiments, the PPRT is Lutathera.A non-exhaustive list of other agents that can be used in PRRT includes, but is not limited to: 111 In-DTPA-octreotide, 90 Y-DOTATOC, 90 Y-DOTATATE, 177 Lu-DOTATOC, 90 Y-lanreotide, 177 Lu-DOTACIN, 111 In-DOTA-BASS, 177 Lu-DOTA-JR11, as well as unsealed radiolabeled sources, such as (but not limited to): 131 iodine, 153 samarium, 223 radium, 225 Actinium / 213 Bismuth, 211 astatine, 166 holmium, 186 rhenium, 188 Rhenium, 67 copper, 149 promethium, 199 gold, 105 rhodium, 77 bromine, 111 Indium, and 123 / 125 Any therapeutic agent that uses an SSA peptide radiolabeled with iodine is included.

[0083] Lutathera can be produced by methods well known to those skilled in the art, exemplary such methods include those described in US 5,804,157 or US 5,830,431.

[0084] The present invention provides a method for treating neuroendocrine tumors, comprising administering to a subject (e.g., a subject in need of treatment) a therapeutically effective amount of PPRT in combination with an inhibitor of the PD-1 / PD-L1 / CTAL-4 pathway. In certain embodiments, the neuroendocrine tumor is a pancreatic neuroendocrine tumor. In certain embodiments, the neuroendocrine tumor is a carcinoid. In certain embodiments, the neuroendocrine tumor is a pulmonary neuroendocrine tumor. As a non-limiting example, the pulmonary neuroendocrine tumor may be SCLC. The present invention is particularly useful for treating neuroendocrine tumors that overexpress SSTRs on the cell surface, such as (but are not limited to) pituitary adenoma, gastrointestinal and pancreatic endocrine carcinoma (GEPNET tumor), lung NET, paraganglioma, pheochromocytoma, small cell lung cancer, medullary thyroid carcinoma, breast cancer, prostate cancer, and malignant lymphoma. In certain embodiments, the subject is a human. In certain embodiments, the PPRT is Lutathera.

[0085] The present invention further provides a method for inhibiting neuroendocrine tumor growth in a subject using a therapeutically effective amount of PPRT in combination with an inhibitor of the PD-1 / PD-L1 / CTLA-4 pathway. In certain embodiments, the method for inhibiting neuroendocrine tumor growth comprises contacting tumor cells in a subject in vitro with a therapeutically effective amount of one or both of PPRT and an inhibitor of the PD-1 / PD-L1 / CTLA-4 pathway. For example, an immortalized neuroendocrine tumor cell line is cultured in a medium supplemented with PPRT to inhibit tumor growth. In some embodiments, neuroendocrine tumor cells are isolated from a patient sample, such as a tissue biopsy, pleural effusion, or blood sample, and cultured in a medium supplemented with PPRT and / or an inhibitor of the PD-1 / PD-L1 / CTLA-4 pathway to inhibit tumor growth.

[0086] In some embodiments, the method for inhibiting neuroendocrine tumor growth comprises contacting a neuroendocrine tumor or tumor cells in vivo with a combination therapy of the present invention. In certain embodiments, contacting a neuroendocrine tumor or tumor cells with an inhibitor of the PPRT and PD-1 / PD-L1 / CTLA-4 pathway is carried out in an animal model. For example, an inhibitor of the PPRT and PD-1 / PD-L1 / CTLA-4 pathway is grown in immunodeficient mice (e.g., NOD / SCID mice) to inhibit neuroendocrine tumor growth. Therapeutic agents can be administered to neuroendocrine tumor xenografts. In some embodiments, neuroendocrine tumor cancer stem cells are isolated from patient samples, such as tissue biopsies, pleural effusions, or blood samples, and injected into immunodeficient mice, which are then administered the combination therapy of the present invention (i.e., PPRT and PD-1 / PD-L1 / CTLA-4 pathway inhibitors) to inhibit neuroendocrine tumor cell growth. In some embodiments, PPRT and / or PD-1 / PD-L1 / CTLA-4 pathway inhibitors are administered simultaneously with or shortly after the introduction of tumorigenic cells into the animal to prevent neuroendocrine tumor growth. In some embodiments, PPRT and / or PD-1 / PD-L1 / CTLA-4 pathway inhibitors are administered as therapeutic agents after tumorigenic cells have grown to a specified size.

[0087] In certain embodiments, the method for inhibiting neuroendocrine tumor growth comprises administering to a subject a therapeutically effective amount of an inhibitor of PPRT and PD-1 / PD-L1 / CTLA-4. In certain embodiments, the subject is a human. In certain embodiments, the subject has a neuroendocrine tumor or has had a tumor removed.

[0088] In certain embodiments, the neuroendocrine tumor is a pancreatic neuroendocrine tumor. In certain embodiments, the neuroendocrine tumor is a carcinoid. In certain embodiments, the neuroendocrine tumor is a pulmonary neuroendocrine tumor. In certain embodiments, the neuroendocrine tumor is an NSCLC.

[0089] Furthermore, the present invention provides a method for reducing the tumorigenicity of a neuroendocrine tumor in a subject, the method comprising administering to the subject a therapeutically effective amount of PPRT and a PD-1 / PD-L1 inhibitor. In certain embodiments, the neuroendocrine tumor contains cancer stem cells. In certain embodiments, the frequency of cancer stem cells in the neuroendocrine tumor is reduced by administering the agent. In certain embodiments, the PPRT is Lutathera.

[0090] Thus, the present invention also provides a method for reducing the frequency of cancer stem cells in a neuroendocrine tumor, comprising contacting the tumor with an effective amount of PPRT and an inhibitor of the PD-1 / PD-L1 / CTLA-4 pathway.

[0091] As described herein, PPRT is administered in combination with an inhibitor of the PD-1 / PD-L1 pathway. In such methods, PPRT can be administered prior to, concurrently with, and / or subsequent to the administration of the PD-1 / PD-L1 / CTLA-4 inhibitor. Pharmaceutical compositions comprising PPRT and a PD-1 / PD-L1 / CTLA-4 inhibitor are also provided. Combination treatment with PPRT and a PD-1 / PD-L1 / CTLA-4 inhibitor is expected to have a synergistic effect on the treatment of NETs.

[0092] It will be appreciated that the combination of PPRT and a PD-1 / PD-L1 / CTLA-4 inhibitory agent can be administered in any order or simultaneously. In selected embodiments, PPRT and PD-1 / PD-L1 / CTLA-4 are administered to patients who have previously received treatment with other anti-cancer agents. In certain other embodiments, PPRT and a PD-1 / PD-L1 / CTLA-4 inhibitory agent are administered substantially simultaneously or concomitantly. For example, a subject may be given PPRT while undergoing a course of treatment with a PD-1 / PD-L1 / CTLA-4 inhibitory agent. Furthermore, it is contemplated that a subject may have already received or may be concurrently receiving other forms of cancer therapy, such as chemotherapy. In certain embodiments, PPRT is administered within one year of treatment with a PD-1 / PD-L1 / CTLA-4 inhibitory agent. In certain alternative embodiments, PPRT is administered within 10, 8, 6, 4, or 2 months of any treatment with a PD-1 / PD-L1 / CTLA-4 inhibitory agent and / or an additional anti-cancer agent. In certain other embodiments, PPRT is administered within 10, 8, 6, 4, or 2 months of any treatment with a PD-1 / PD-L1 / CTLA-4 inhibitory agent and In some embodiments, PPRT is administered within 4, 3, 2, or 1 week of any treatment with the PD-1 / PD-L1 / CTLA-4 inhibitory agent and / or additional anti-cancer agent. In some embodiments, PPRT is administered within 5, 4, 3, 2, or 1 day of any treatment with the PD-1 / PD-L1 / CTLA-4 inhibitory agent and / or additional anti-cancer agent. It will further be appreciated that PPRT and the PD-1 / PD-L1 / CTLA-4 inhibitory agent and / or additional anti-cancer agent or treatment may be administered to a subject within hours or minutes (i.e., substantially simultaneously).

[0093] In addition to administering a combination of PPRT and at least one PD-1 / PD-L1 inhibitor, it may also be useful to administer an additional anticancer drug. Useful classes of anticancer drugs include, for example, antitubulin agents, auristatins, DNA minor groove binders, DNA replication inhibitors, alkylating agents (e.g., platinum complexes, e.g., cis-platin, mono-, di-, and trinuclear platinum complexes, and carboplatin), anthracyclines, antibiotics, antifolates, antimetabolites, chemotherapy sensitizers, duocarmycins, etoposide, fluoropyrimidines, ionophores, lexitropsin, nitrosoureas, platinol, performing compounds, purine antimetabolites, puromycin, radiosensitizers, steroids, taxanes, topoisomerase inhibitors, vinca alkaloids, etc. In certain embodiments, the second anti-cancer agent is an antimetabolite, an antimitotic, a topoisomerase inhibitor, or an angiogenesis inhibitor.

[0094] Anti-cancer agents that may be administered in combination with PPRT and PD-1 / PD-L1 / CTLA-4 inhibition include chemotherapeutic agents. Thus, in some embodiments, a method or treatment involves the combined administration of PPRT and PD-1 / PD-L1 / CTLA-4 inhibitors and a chemotherapeutic agent or cocktail of multiple different chemotherapeutic agents. Treatment with PPRT can occur prior to, concurrently with, or subsequent to the administration of these other therapies. Chemotherapy contemplated by the present invention includes chemicals or drugs known in the art and commercially available, such as gemcitabine, irinotecan, doxorubicin, 5-fluorouracil, cytosine arabinoside ("Ara-C"), cyclophosphamide, thiotepa, busulfan, cytoxin, taxol, methotrexate, cisplatin, melphalan, vinblastine, and carboplatin. Concomitant administration can include co-administration in a single pharmaceutical formulation or using separate formulations, or sequential administration in any order, but generally within a time period that allows all active agents to simultaneously exert their biological activity. Preparation and dosing schedules for such chemotherapeutic agents can be used according to the manufacturer's instructions or as empirically determined by the skilled practitioner.

[0095] Chemotherapeutic agents useful in the present invention include, but are not limited to, alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylameramines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaoramide, and trimethylolomelamime. amines), nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trofosfamide, uracil mustard, etc.; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, etc.; antibiotics such as aclacinomycin, actinomycin, ausramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chlorambucil ... romomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, chelamycin, rodorubicin, streptonigrin, streptozotocin, tubercidin, ubenimex, zinostatin, zorubicin, and the like; antimetabolites, e.g., methotrexate, folic acid analogues, such as denopterin, methotrexate, pteropterin, trimetrexate, etc.; purine analogues, such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, etc.; pyrimidine analogues, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU, etc.; androgens, such as calsterone, dromostanopropionate, etc. ron, epitiostanol, mepitiostane, testolactone, etc.; anti-adrenal agents, such as aminoglutethimide, mitotane, trilostane, etc.; folic acid supplements such as furoic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformitine; elliptinium acetate; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxazone Introne; Mopidamol; Nitracrine; Pentostatin; Fenameth; Pirarubicin; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK; Razoxane; Sizofuran; Spirogermanium; Tenuazonic acid; Triazicone; 2,2',2"-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa;Taxoids, such as paclitaxel (TAXOL, Bristol-Myers Squibb Oncology, Princeton, NJ), and doxetaxel (TAXOTERE, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11; the topoisomerase inhibitor RFS2000; difluoromethylornithine (OMFO); retinoic acid; esperamycin; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Chemotherapeutic agents also include antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens including tamoxifen, raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Farestone); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0096] In certain embodiments, the therapeutic agent is a kinase inhibitor. In certain embodiments, the kinase inhibitor is a multi-targeted receptor tyrosine kinase inhibitor. Kinase inhibitors include but are not limited to sunitinib (sold by Pfizer as Sutent), pazopanib, crizotinib, and dasatinib. In certain embodiments, the second anticancer agent is sunitinib.

[0097] In certain embodiments, the therapeutic agent is an inhibitor of the mammalian target of rapamycin (mTOR). mTOR inhibitors include, but are not limited to, temsirolimus, sirolimus In certain embodiments, the second anticancer agent is everolimus.

[0098] In certain embodiments, the therapeutic agent is a somatostatin analogue.Somatostatin analogues act through the interaction with somatostatin's specific high-affinity membrane receptor.Somatostatin analogues include but are not limited to octreotide, somatuline and RC160 (octastatin).In certain embodiments, the second anticancer agent is octreotide.

[0099] In certain embodiments, the chemotherapeutic agent is a topoisomerase inhibitor.Topoisomerase inhibitors are chemotherapeutic agents that inhibit the action of topoisomerase enzymes (for example, topoisomerase I or II).Topoisomerase inhibitors include, but are not limited to, doxorubicin HCl, daunorubicin citrate, mitoxantrone HCl, actinomycin 0, etoposide, topotecan HCl, teniposide (VM-26), and irinotecan.In certain embodiments, the second anticancer agent is irinotecan.

[0100] In certain embodiments, the chemotherapeutic agent is an alkylating agent, hi certain embodiments, the chemotherapeutic agent is temozolomide.

[0101] In certain embodiments, the chemotherapeutic agent is an antimetabolite.An antimetabolite is a chemical compound whose structure is similar to that of a metabolite required for normal biochemical reactions, but is different enough to interfere with one or more normal functions of cells, such as cell division.Antimetabolites include, but are not limited to, gemcitabine, fluorouracil, capecitabine, methotrexate sodium, ralitrexed, pemetrexed, tegafur, cytosine arabinoside, thioguanine (GlaxoSmithKline), 5-azacytidine, 6-mercaptopurine, azathioprine, 6-thioguanine, pentostatin, fludarabine phosphate, and cladribine, and any pharmaceutically acceptable salt, acid, or derivative thereof.In certain embodiments, the second anticancer agent is gemcitabine. In certain embodiments, the tumor being treated is a pancreatic neuroendocrine tumor and the second anti-cancer agent is an antimetabolite (e.g., gemcitabine).

[0102] In certain embodiments, the chemotherapeutic agent is an antimitotic agent, including, but not limited to, an agent that binds to tubulin. As a non-limiting example, the agent includes a taxane. In certain embodiments, the agent includes paclitaxel or docetaxel, or a pharmaceutically acceptable salt, acid, or derivative of paclitaxel or docetaxel. In certain embodiments, the agent is paclitaxel (TAXOL), docetaxel (TAXOTERE), albumin-bound paclitaxel (e.g., ABRAXANE), DHA-paclitaxel, or PG-paclitaxel. In certain alternative embodiments, the antimitotic agent includes a vinca alkaloid, such as vincristine, vinblastine, vinorelbine, or vindesine, or a pharmaceutically acceptable salt, acid, or derivative thereof. In some embodiments, the antimitotic agent is an inhibitor of Eg5 kinesin or an inhibitor of a mitotic kinase, such as Aurora A or Plk1.

[0103] In certain embodiments, the treatment involves the combined administration of PPRT and a PD-1 / PD-L1 / CTLA-4 inhibitor as described herein, and radiation therapy. Treatment with PPRT can be administered prior to, concurrently with, or subsequent to the administration of radiation therapy. Any administration schedule for such radiation therapy can be used as determined by a skilled practitioner.

[0104] In some embodiments, the second anti-cancer agent comprises an antibody. Thus, treatment can involve the combined administration of PPRT and a PD-1 / PD-L1 / CTLA-4 inhibitor with an antibody against a tumor-associated antigen, including, but not limited to, an antibody that binds to EGFR, ErbB2, HER2, DLL4, Notch, and / or VEGF. In certain embodiments, the second anti-cancer agent is an antibody that is an angiogenesis inhibitor (e.g., an anti-VEGF antibody). In certain embodiments, the second anti-cancer agent is an inhibitor of Notch signaling. In certain embodiments, the second anti-cancer agent is AVASTIN (bevacizumab), HERCEPTIN (trastuzumab), VECTIBIX (panitumumab), or ERBITUX (cetuximab). Combined administration can include co-administration in a single pharmaceutical formulation or using separate formulations, or sequential administration in any order, but generally within a time period that allows all active agents to simultaneously exert their biological activity.

[0105] Additionally, treatment may include administration of one or more cytokines (e.g., lymphokines, interleukins, tumor necrosis factors, and / or growth factors), or may involve surgical removal or cytoreductive treatment of cancer cells, such as (chemoradio)embolization, radiofrequency ablation, and high-intensity focused ultrasound (HIFU) ablation, or any other therapy deemed necessary by the treating physician.

[0106] Appropriate dosages described herein for treating disease depend on the type of neuroendocrine tumor being treated, the severity and course of the neuroendocrine tumor, the responsiveness of the neuroendocrine tumor, whether PPRT and PD-1 / PD-L1 / CTLA-4 are administered for therapeutic or prophylactic purposes, previous therapy, the patient's medical history, etc., all at the discretion of the treating physician. PPRT and PD-1 / PD-L1 / CTLA-4 inhibitors can be administered once or over a series of treatments lasting from several days to several months, or until a cure is achieved or shrinkage of the neuroendocrine tumor (e.g., a reduction in tumor size) is achieved. Optimal dosing schedules can be calculated from measurements of drug accumulation in the patient's body and will vary depending on the relative efficacy of individual dosing regimens.

[0107] The administering physician can easily determine the optimal dosage, dosing method, and repetition rates. In certain embodiments, the dosage is 0.01 μg to 100 mg per kg of body weight and can be given one or more times daily, weekly, monthly, or yearly. In certain embodiments, the PPRT and PD-1 / PD-L1 / CTLA-4 inhibitory agent are given once every two weeks or once every three weeks. In certain embodiments, the dosage of the PPRT and PD-1 / PD-L1 / CTLA-4 inhibitory agent is about 0.1 mg to about 20 mg per kg of body weight. The treating physician can estimate the dosing repetition rate based on the measured residence time and concentration of the drug in bodily fluids or tissues.

[0108] Typically, PRRT, including Lutathera, is given in cycles, with each cycle containing 3.7 to 7.4 GBq administered intravenously. Typically, a cumulative therapeutic dose of approximately 30 GBq can be easily separated into 4 to 6 cycles, each administered every 5 to 12 weeks. It should be understood that longer intercycle intervals, as long as 6 months or even years, can be used. Furthermore, patients may be treated with multiple rounds of 4 to 6 cycles several months or years after the first set of treatment. The second and subsequent sets of treatment may use the same dose or different doses depending on the experience of the center and the characteristics and therapeutic needs of each patient.

[0109] Anti-PD-1 nivolumab is typically administered intravenously at a dose of approximately 3 mg / kg every 2–3 weeks for an initial period of 2 years, followed by maintenance every 12 weeks after initial treatment. Maintenance therapy is frequently used. It should be understood that these dosing regimens will vary according to the patient's response to treatment and at the discretion of the treating clinician. The recommended dose of ipilimumab for the treatment of unresectable or metastatic melanoma is 3 mg / kg administered intravenously over 90 minutes every 3 weeks for a total of 4 doses.

[0110] PPRT and PD-1 / PD-L1 / CTLA-4 inhibitors (e.g., antibodies and soluble receptors) can be formulated into pharmaceutical compositions by any suitable method known in the art. In certain embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable vehicle. The pharmaceutical composition finds use in inhibiting neuroendocrine tumor growth and treating neuroendocrine tumors in human patients. [Example]

[0111] Example 1: Lutathera is administered at a fixed dose of 7.4 GBq (every 12 weeks) to a cumulative dose tolerated by the patient (maximum 29.6 GBq). Nivolumab is administered at a dose of 3 mg / kg twice for each Lutathera treatment: one dose 7 days before (d-7) and the other 7 days after (d+7) the Lutathera administration, with the goal of achieving effective PD-1 / PD-L1 blockade but also requiring no overlap with the anticipated lymphocyte nadir associated with the lymphopenia-inducing effect of Lutathera. Studies have shown that intravenous administration of amino acids has a renal protective effect. The amino acid (containing lysine and arginine) infusion can be given 30-45 minutes before administering 177Lu-DOTATATE and can last for 3-4 hours. References [ka] [ka]

Claims

[Claim 1] 1. A pharmaceutical composition for treating a cancer that overexpresses somatostatin receptors, comprising a peptide receptor radionuclide therapy (PRRT) agent, wherein the pharmaceutical composition is administered to a patient in combination with an antibody that inhibits the PD-1 pathway, wherein the PRRT agent is [177]lutetium-DOTA[O]-Tyr[3]-octreotate (177Lu-DOTATATE), the antibody that inhibits the PD-1 pathway is nivolumab, and the cancer is small cell lung cancer (SCLC).

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