Table of Contents  

June: Cell therapy for cancer – our synthetic future

Introduction

It is widely accepted that the immune system has evolved cellular and humoral mechanisms that can evoke natural immune responses to tumours.1 However, in most instances, vaccines fail to induce rejection of established tumours.2 Adoptive T-cell transfer, a term coined by Billingham, Brent and Medawar,3 has the potential to overcome one of the significant limitations associated with vaccine-based strategies, specifically the requirement to de novo activate and expand a tumour antigen-specific T-cell response in patients who are often immunocompromised. Mitchison4 first reported the targeting of cancer through the adoptive transfer of lymphocytes in rodent models over 50 years ago.

The first generation of chimeric antigen receptors (CARs) were engineered receptors comprising a single-chain variable fragment (where the variable portions of the light and heavy chains of a high-affinity antibody are connected by a linker sequence), a transmembrane domain and the signalling domain of CD3ζ.5 Second-generation CARs have included the costimulatory domains derived from CD28, 4-1BB or OX40 to optimize T-cell activation, and these have improved function in vivo, particularly against more aggressive tumours that do not express costimulatory molecules. Third-generation CARs also include the signalling domains of a third molecule such as tumour necrosis factor (TNF)-receptor family members including 4-1BB or OX40; these have less potent cytotoxic activity but persist longer in vivo.6 However, because CARs are antibody based, the high-affinity single-chain variable fragments derived from antibody sequences typically have been directed at native surface antigens, and this restricts suitable targets to proteins or epitopes displayed on the surface of the target cell.

Results to date

A number of clinical trials of CAR T cells, directed at a variety of antigens, are under way.7,8 Several centres have focused some effort towards studies on CD19-directed CAR T cells and on other B-cell markers such as immunoglobulin light chains and CD20, in part because haematopoietic cells have been extensively characterized and the expression of their surface molecules is often dependent on lineage. Multiple reviews of CD19 CAR T-cell trials are available elsewhere914 and are discussed only in aggregate here. One issue that has complicated the interpretation of CD19 CAR T-cell trials is that each centre has developed its own CAR, with different single-chain variable fragments to mediate antigen binding, different signalling domains, different modes of CAR gene introduction into T cells, different conditioning regimens and different interventions post CAR T-cell infusion. However, some B-cell malignancies are more consistently clinically responsive to CD19 CAR T cells. For example, trials in chronic lymphocytic leukaemia (CLL) have yielded very mixed clinical results, whereas trials in acute lymphoblastic leukaemia (ALL) have yielded impressive responses in multiple centres.1517 In one case of paediatric ALL, a patient relapsed with CD19-negative disease, indicating that CD19 CAR T cells effected very strong selective pressure on cells expressing the CD19 target.17 In contrast, tumour cells from all non-responding patients with CLL appear to retain CD19 expression. Both fate and persistence of CAR T cells seem to have a significant impact on the clinical responses, but the determinants of these variables are still unclear. It is likely that factors such as the input cell population and the tumour microenvironment play prominent roles in determining CAR T-cell persistence and, therefore, clinical efficacy even when other variables (type of CAR T cell and manufacturing process) are controlled.

Summary

The field of T-cell engineering is now entering adolescence, and creative solutions to many of the current limitations are sure to emerge. For example, one group of investigators hypothesized that, in graft-versus-host disease (GvHD) following allogeneic bone marrow transplant, T cells could cause damage to the tissues only if they trafficked to those tissues. When tissue trafficking was reduced via administration of a drug blocking CCR5 [maraviroc (Celsentri®, ViiV Healthcare, Brentford, UK], GvHD was ameliorated in early studies,18 and confirmatory studies are under way. The incorporation of chemokine receptors to alter tumour-specific T-cell migration is also under investigation, as are mechanisms to improve T-cell resistance to inhibitory signals, perhaps to avoid conditioning chemotherapy regimens.

The future of CAR therapies looks bright, in part because early studies have shown that CAR T cells are quite potent. Strategies to expedite the discovery of suitable surface antigens may make CAR T cells more widely applicable. The generation of single-chain variable fragments to perform rapid throughput testing on tumours and on normal tissues to identify potential off-tumour reactivity may also increase the applicability of CAR therapies.

Conflict of interest

Carl June is the inventor of technologies used to treat cancer with engineered T cells. The patents are listed below. This technology has been assigned to the University of Pennsylvania and the US Government, and some of the technology has been licensed by Novartis. The conflict is managed by the University of Pennsylvania according to policy and procedures.

Inventions and detailed technology disclosure:

  1. June C, Thompson C, Kim S, inventors; US Government, ONR, assignee. Methods for Modulating Expression of Exogenous DNA in T Cells, 1995. USPTO 08/435,095, CIP issued in 2006.

  2. June CH, inventor; Methods for modulating T cell responses by manipulating intracellular signal transduction. Filed 1 May 1995, Australia patent 706761, issued 1999.

  3. June CH, Craighead N, inventors; US Government, ONR, assignee. Murine hybridoma and antibody binding to CD28 receptor secreted by the hybridoma and method of using the antibody. Filed January 17, 1996, US patent 5,948,893, issued 1999.

  4. June CH, Thompson CB, Nabel GJ, Gray GS, Rennert PD, Freeman GJ, inventors; Methods for selectively stimulating proliferation of T cells. Filed June 3, 1994, US patent 5,858,358.

  5. June CH, Thompson CB, inventors; US Government, ONR, assignee. Methods for Modulating T Cell Survival by Modulating Bcl-X L Protein Level. Filed June 7, 1995, US patent 6,143,291 issued 2000.

  6. June C, Thompson C, Nabel GJ, Gray G, Rennert P, inventors; US Government, ONR, assignee. Methods for Inducing a Population of T Cells To Proliferate Using Agents which Recognize TCR/CD3 and Ligands which Stimulate an Accessory Molecule on the Surface of the T Cells. Filed March 10, 1995, US patent 6,352,694 B1, issued 2002.

  7. June CH, inventor; Methods for modulating T cell responses by manipulating intracellular signal transduction. US patent 6,632,789, issued 2003.

  8. June CH, Thompson CB, Nabel GJ, Gray GS, Rennert PD, inventors; US Government, ONR, assignee. Methods for selectively stimulating proliferation of T cells. Filed May 4, 1995, US patent 6534055, issued 2003.

  9. June CH, Kim S, Thompson CB, inventors; US Government, ONR, assignee. Methods for transfecting T cells. Filed June 7, 1995, US patent 6692964 B1 issued 2004.

  10. Thompson CB, June CH, inventors; US Government, ONR, assignee. Methods of treating autoimmune disease via CTLA-4Ig. Filed Feb 7, 1995, US patent 6,685,941, issued 2004.

  11. June C, Thompson C, Nabel GJ, Gray GS, Rennert P, inventors; US Government, ONR, assignee. Methods for selectively Stimulating Proliferation of T cells. Filed Jan 26, 1996, US patent 6,905,680, issued 2005.

  12. Carroll RG, Shan X, Danet-Desnoyers G, June C, inventors; Modulation of Regulatory T-Cells by Human IL-18. Filed Sept 14, 2007, PCT Application PCT/US2007/01995.

  13. June CH, Thompson CB, Kim S, inventors; Methods for transfecting T cells. US patent 7172869 B2, issued 2007.

  14. June CH, Thompson CB, Nabel GJ, Gray GS, Rennert PD, inventors; Methods for selectively stimulating proliferation of T cells. US patent 7175843 B2, issued 2007.

  15. June C, Thompson C, Nabel GJ, Gray GS, Rennert P, inventors; US Government, ONR, assignee. Methods for treating HIV infected subjects, filed Oct 22, 2008, USPTO 12/255,861.

  16. Blazar B, June C, Godfrey W, Carroll R, Levine B, Riley J, Taylor P, inventors; Trustees of the University of Pennsylvania, assignee. Regulatory T cells and their use in immunotherapy and suppression of autoimmune responses. Filed Dec 29, 2009, USPTO 12/649,101.

  17. June C, Riley J, Maus M, Thomas AK, inventors; The Trustees of the University of Pennsylvania, assignee. Activation and expansion of T-cells using an engineered multivalent signaling platform. Filed Jan 3, 2003, US patent 7,638,326, issued 2009.

  18. June C, Thompson C, Nabel G, Gray G, Rennert P, inventors; Genetics Institute, Regents of the University of Michigan, The United States of America as represented by the Secretary of the Navy, assignee. Methods for selectively enriching TH1 and TH2 cells. US patent 7,479,269, issued 2009.

  19. Riley J, June C, Blazar B, Hippen KL, inventors; Inducible regulatory T-cell generation for hematopoietic transplants. Filed June 19, 2009, PCT/US2009/047887.

  20. Blazar B, June C, Godfrey W, Carroll R, Levine B, Riley J, Taylor P, inventors; The Trustees of the University of Pennsylvania, assignee. Regulatory T cells and their use in immunotherapy and suppression of autoimmune responses. Filed April 19, 2004; US patent 7,651,855, issued 2010.

  21. Fowler DH, Jung U, Gress RE, Levine B, June C, inventors; Rapamycin-resistant T cells and therapeutic uses thereof. Filed Dec 9, 2005, US patent 7,718,196 B2, issued 2010.

  22. June C, Levine B, Porter D, Kalos M, inventors; University of Pennsylvania, assignee. Use of chimeric antigen receptor-modified T cells to treat cancer. Filed Dec 9, 2010, US Provisional Patent Appl. No. 61/421,470.

  23. June C, Riley J, Maus M, Thomas A, Vonderheide R, inventors; The Trustees of the University of Pennsylvania, assignee. Activation and expansion of T-cells using an engineered multivalent signaling platform as a research tool. Filed June 13, 2003; US patent 7,745,140, issued 2010.

  24. Riley J, June C, Maus M, inventors; The Trustees of the University of Pennsylvania assignee. System and methods for promoting expansion of polyclonal and antigen-specific cytotoxic T lymphocytes in response to artificial antigen presenting cells. Filed Jan 3, 2003, US patent 7670781, issued 2010.

  25. Riley J, June C, Vonderheide R, Aqui N, Suhoski M, inventors; The Trustees of the University of Pennsylvania assignee. Artificial antigen presenting cells and uses therefor. Filed Jan 3, 2003; US patent 7754482 B2, issued 2010.

  26. Riley J, June C, Vonderheide R, Aqui N, Suhoski M, inventors; Trustees of the University of Pennsylvania, assignee. Novel Artificial Antigen Presenting Cells and Uses Therefor. Filed June 8, 2010, USPTO 12/796,445.

  27. Fowler DH, Jung U, Gress RE, Levine B, June C, inventors; DHHS and Trustees of University of Pennsylvania, assignee. Rapamycin-resistant T cells and therapeutic uses thereof. Filed March 30, 2010; US patent 8075921, issued 2011.

  28. June C, Levine B, Porter D, Kalos M, inventors; Use of chimeric antigen receptor-modified T cells to treat cancer. Filed Dec 9, 2011, PCT/US11/64191.

  29. June C, Levine B, Porter D, Kalos M, inventors; Compositions and Methods for Treatment of Chronic Lymphocytic Leukemia. Filed June 29, 2011, U.S. Prov’l Patent Appl. No. 61/502,649.

  30. June CH, Carroll RG, Riley JL, St. Louis DC, Levine BL, inventors; US Government, ONR, assignee. Methods for downregulating CCR5 in T cells with anti-CD3 antibodies and anti-CD28 antibodies. Filed Feb 20, 1998; US patent 7927595, issued 2011.

  31. Riley J, June C, Blazar B, Hippen KL, inventors; Methods to expand a T regulatory cell master cell bank. Filed March 28, 2011, WO2011126806 A1.

  32. Riley J, Paulos CM, June C, Levine B, inventors; ICOS critically regulates the expansion and function of inflammatory human Th17 cells. Filed April 2, 2011, PCT/US11/23744.

  33. Zhao Y, June CH, inventors; Switch Costimulatory Receptors. Filed July 29, 2011. WO2013019615 A2.

  34. Zhao Y, Kalos M, June CH, inventors; University of Pennsylvania, assignee. RNA Engineered T Cells for the Treatment of Cancer. Filed Sept 16, 2011. WO2013040557 A2.

  35. Blazar B, June C, Godfrey W, Carroll R, Levine B, Riley J, Taylor P, inventors; Trustees of the University of Pennsylvania, assignee. Regulatory T cells and their use in immunotherapy and suppression of autoimmune responses. Filed December 29, 2009, US patent 8129185, issued 2012.

  36. Frigault MJ, Scholler J, June C, inventors; Compositions and Methods for Generating a Persisting population of T Cells Useful for the Treatment of cancer. Filed Feb 21, 2012, PCT/US2013/027337.

  37. Guedan S, Zhao Y, Scholler Y, June C, inventors; Use of ICOS based CARs to enhance antitumor activity and CAR persistence. Filed Feb 21, 2012, WO2013126733 A1, PCT/2013/027366.

  38. Kawalekar O, Zhao Y, Scholler J, June C, inventors; Double Transgenic T Cells Comprising a CAR and a TCR and Their Methods of Use. Filed Feb 21, 2012.

  39. Levine B, June C, inventors; Methods for treating progressive multifocal leukoencephalopathy US patent 8415150, issued 2013.

  40. Zhao, Y, Kalos, M, Lui, X, June C, inventors; Topical delivery of therapeutic molecules using mRNA engineered T cells. disclosure to CTT: Sept 5, 2013. Penn ref 14-6825.

  41. Zhao, Y, Liu, X, June, C, inventors; Enhanced antitumor effects of TCR RNA electroporated T lymphocytes. disclosure to CTT: Jan 6, 2014. Penn ref pending.

  42. Zhao Y, Liu, X, June C. Stimulating and expanding high quality T cells directly by RNA electroporation. disclosures to CTT: Jan 10, 2014. Penn ref pending.

  43. Zhao, Y, Shedlock, D, June C, inventors; Enhanced antigen presenting ability of RNA CAR T cells by co-introduction of costimulatory molecules. disclosure to CTT: Jan 10, 2014. Penn ref No 14-6882.

  44. June, C, Zhao, Liu, X, inventors; Enhancing activity of CAR T cells by co-introducing a bispecific antibody. Patent No: WO2014011988 A2.

  45. June, CH, Levine, BL, Kalos, MD, Zhao, Y, inventors; Epitope spreading associated with CAR T-cells. Patent No: WO2014011993 A2.

  46. Aqui, N, June, CH, Riley, JL, Suhoski, M, and Vonderheide, RH, inventors; Novel artificial antigen presenting cells and uses therefor. May 25, 2005. WO2005118788 A3.

  47. Carroll, RG, June, CH, and Riley, JL, inventors; Methods, compositions and kits relating to antigen presenting tumor cells. publication date Jul 10, 2008, WO2008027456 A3.

  48. June, C, Carroll, R, Riley, J, Louis, DS, and Levine, B, inventors; Methods for modulating expression of an HIV-1 fusion cofactor. publication date Sep 14, 2006, US20060204500 A1.

  49. June, CH, Riley, JL, Maus, M, Thomas, A, and Vonderheide, R, inventors; Activation and expansion of T-cells using an engineered multivalent signaling platform as a research tool. US patent US8637307 B2, issued 2014.

  50. Riley, J, June, C, and Maus, M, inventors; Activation and expansion of T-cells using an agent that provides a primary activation signal and another agent that provides a co-stimulatory signal. US patent number US7670781 B2, issued 2010.

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