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Using targeted radiotherapy (TRT) to drive Anti-tumor immune response to immunotherapies

A targeted and immunomodulatory technology, applied in radiotherapy, anti-tumor drugs, anti-animal/human immunoglobulin, etc., can solve problems such as xRT cannot be used in combination, destroy immunotherapy, systemic immunosuppression, etc.

Pending Publication Date: 2020-08-21
WISCONSIN ALUMNI RES FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, xRT cannot be used effectively in combination with in situ vaccination approaches in the presence of multiple tumors, especially if the number of tumors is not small, or if the location of one or more tumors is not precisely known, or if xRT Delivery to all tumor sites is not feasible
Furthermore, administration of xRT to all tumor sites in patients with metastatic disease may result in systemic immunosuppression, defeating the primary purpose of systemically administered immunotherapy

Method used

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  • Using targeted radiotherapy (TRT) to drive Anti-tumor immune response to immunotherapies
  • Using targeted radiotherapy (TRT) to drive Anti-tumor immune response to immunotherapies
  • Using targeted radiotherapy (TRT) to drive Anti-tumor immune response to immunotherapies

Examples

Experimental program
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Effect test

Embodiment 1

[0221] Example 1: Background Support Data

[0222] The Sondel lab has demonstrated that tumor-specific mAb+IL2 activates innate immune cells to mediate ADCC in mice [2], with clinical benefit in children with neuroblastoma [3]. In mice, intravenous administration of hu14.18-IL2 IC was more effective than intravenous administration of anti-GD2 mAb+IL2 [2,10]. This can provide significant antitumor effects in recently established very small GD2+ tumors or very small micrometastases, possibly explaining the clinical utility of this approach in patients who are in remission but are at high risk of recurrence [3]. Target measurably large tumors [i.e. ~50 mm when injected IC intratumorally (IT-IC) rather than IV (intravenously) 3 GD2+ tumors] have a stronger anti-tumor effect [4,5].

[0223] We are now focusing on ways to provide benefit to larger macroscopic tumors. Established 5 weeks ago to carry medium size (200mm 3 ) B78 melanoma tumors in mice that did not respond to IV-I...

Embodiment 2

[0228] Example 2: Determining the dose of xRT

[0229] Our data suggest these four hypotheses: (1) the dose of xRT we use to treat individual tumors causes modest direct in vivo tumor death and increases susceptibility to immune-mediated death (via ADCC and T cells); (2) Strong T cell responses provided by the addition of IT-IC but not IT mAbs suggest that in the presence of IL2, mAb binding to irradiated tumor cells promotes antigen presentation and enhanced induction of adaptive immunity; (3) presence of a second tumor As a result, xRT+IT-IC can hardly cause any antitumor effect on the first tumor, which is mainly due to tolerance caused by the systemic effects of immunosuppressive cells present in the second tumor [such as Treg and possibly myeloid-derived suppressor cells ( MDSC)]; by consuming Treg( Figure 4 ) or irradiated second tumor ( image 3 ) can avoid this tolerance; (4) the dose of RT required for the second tumor to avoid tolerance can be much lower than the ...

Embodiment 3

[0241] Determined with TRT and immunosuppression from TRT in C57BL / 6 mice 131 Dose of I-NM404 and evaluate the effect on immune function dosimetry

[0242] 131 I-NM404 showed selective in vitro uptake in >95% of tumor lines (human and mouse), poor uptake by non-malignant cells, and similar tumor specificity was observed in vivo. This includes selective in vivo uptake by B78 tumors ( Figure 5 ). In our preliminary dosimetry studies, we administered C57BL / 6 mice 124 I-NM404, and characterize the time course of TRT exposure by serial PET / CT imaging (eg Figure 5 shown). Monte Carlo dosimetry calculations based on this study [16-18] show that during the 4-week decay period, about 60 μCi of 131 I-NM404 delivered approximately 3Gy to established B78 tumors. After these 4 weeks, the remaining TRT dose to B78 tumors will be less than 0.25 Gy. We will use xRT to replicate the data we obtained in a dual tumor model ( image 3 ), but using the lowest possible dose of targeted ...

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Abstract

The disclosed method of treating a malignant solid tumor in a subject includes the steps of administering to the subject an immunomodulatory dose of a radioactive phospholipid ether metal chelate, a radiohalogenated phospholipid ether, or other targeted radiotherapy (TRT) agent that is differentially retained within malignant solid tumor tissue, and performing immunotherapy in the subject by systemically administering to the subject an immunostimulatory agent, such as an immune checkpoint inhibitor. In a non-limiting example, the radioactive phospholipid ether metal chelate or radiohalogenatedphospholipid ether has the formula: wherein R1 comprises a chelating agent that is chelated to a metal atom, wherein the metal atom is an alpha, beta or Auger emitting metal isotope with a half-lifeof greater than 6 hours and less than 30 days, or wherein R1 comprises a radioactive halogen isotope. In one such embodiment, a is 1, n is 18, m is 0, b is 1, and R2 is -N+(CH3)3.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Application Serial No. 15 / 809,427, filed November 10, 2017, which is hereby incorporated by reference in its entirety. [0003] Statement Regarding Federal Funding [0004] research or development [0005] This invention was made with government support under OD024576 and CA197078 awarded by the National Institutes of Health. The government has certain rights in this invention. technical field [0006] The present disclosure generally relates to methods of treating cancer. In particular, the present disclosure relates to methods of treating cancer in a subject that includes one or more malignant solid tumors by (1) systemically administering to the subject an immunomodulatory dose of a targeted radiotherapy (TRT) agent, e.g., by radioactive metal chelates, radiohalogenated compounds, radiolabeled antibodies, or radioisotopes that are differentially uptaken and retained in solid ...

Claims

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Application Information

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IPC IPC(8): A61K51/04A61P35/00A61P35/04A61K39/395C07K16/28A61N5/10
CPCA61N5/1001A61K9/0019A61K51/0408A61K51/0497C07K16/3084A61N2005/1021A61N2005/1098C07K2317/24C07K2319/74A61K51/0482A61K45/06A61P35/00
Inventor J·魏歇特P·松德尔R·帕特尔Z·莫里斯P·卡尔森R·赫南德茲J·格鲁得辛斯基
Owner WISCONSIN ALUMNI RES FOUND
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