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The immune checkpoint landscape in 2015: combination therapy


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A comprehensive workshop presentation on approved and developing therapeutics in immuno-oncology, presented at ICI Boston 2015

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The immune checkpoint landscape in 2015: combination therapy

  1. 1. 03-24-2015 Paul D. Rennert Immune Checkpoint Inhibitors and the Evolution of Combinatorial Immuno-Oncology
  2. 2. • The biology and utility of immune checkpoint modulation  drivers and critical issues in the evolution of cancer care  dissociating efficacy from toxicity • Case study: immune checkpoint inhibitors in melanoma • Combination immunotherapy  efficacy and toxicity profiles – can we improve both?  combinations with other therapeutic modalities  tumor cells, lymphocytes, the tumor microenvironment • Future directions and new targets What we'll cover 2
  3. 3. Combinatorial – combination therapy is critical, and not just immune checkpoint combinations  Pro: agnostic and opportunistic as to type of therapy used in combination  Con: there is currently little data to inform combo treatment choices Immuno-oncology – the therapeutic approach targets the immune system  Pro: novel immuno-modulatory targets will broaden the therapy toolkit  Con: we don't know how to sort patients yet, and the choices made may have unique toxicities  diverse indications with a wide variety of SOC  complex indication subtypes with unique genetics, few other biomarkers  in all cases, unique patients 3 Immune checkpoint therapeutics are a component of combinatorial immuno-oncology What does that mean?
  4. 4. primers • cytotoxic • cytokines • vaccines checkpoints • CTLA4 • PD-1/PD-L1 • TIM3, many others • other suppressors expanders • TNFRs • cytokines • CAR-T • BiTEs - Tumor cells - Stromal cells/ECM - Lymphocytes - Therapeutics Big Picture: Immune Checkpoint Modulation 4
  5. 5. primers • cytotoxics • cytokines • vaccines checkpoints • CTLA4 • PD-1 expanders • TNFRs • CAR T • BiTEs Idealized picture of combination immunotherapy 5 patient combo
  6. 6. Idealized picture of combination immunotherapy 6 combo synergy • this is what preclinical models show – we cannot overinterpret those models and acknowledge that these data only generate clinical hypotheses • patient by patient analyses show dramatic variability in genetics, mutation burden, immune profile • nonetheless, some combinations have already produced impressive results
  7. 7. Complex indications, complex patients 7 driver mutations in metastatic melanoma and in lung cancers
  8. 8. Complex indications, complex patients 8 expression of lymphocyte markers and PD-L1 in NSCLC but this picture is highly variable  degree of infiltration (starting at none)  geography of infiltration (marginal, interstitial, stromal, excluded)  functionality of infiltrates (PD-1, TIM-3, LAG3) T cells NK cells CD3+/CD8+ T cells
  9. 9. Complex indications, complex patients 9Galon et al 2013. Immunity 39: 11-26 CD3+ CD8+
  10. 10. Such compexity offers significant challenge, but also opportunity, for new drugs to have a positive impact back to our combinatorial landscape.... 10
  11. 11. primers • cytokines • vaccines • cytotoxics expanders • TNFRs • CAR T • BiTEs Checkpoints Dominate.... 11 checkpoints • CTLA4 • PD-1 • Inhibition appears to be dominant over activation  Preclinical models support this view  Early clinical data support this view, e.g. monotherapeutic activity of TNFR agonists is low  Even CAR T cells can be shut down by immune checkpoint expression • We don't yet understand the impact of removing constraints on NK cell activity and on immuno- suppression imposed by stromal cells
  12. 12. primers • cytokines • vaccines • cytotoxics checkpoints • CTLA4 • PD-1 • TIM3 etc expanders • TNFRs • CAR-T • BiTEs Chemotherapy Radiation Therapy Targeted Therapy other (e.g SCT) immune modulation does not exist in a vaccuum 12
  13. 13. Surgery Debulking Chemotherapy Irradiation Targeted Tx Transplant Indication Genetics Line Age 13 Patient So here's a patient...
  14. 14. 14 high low low high Efficacy/Tolerability Newly diagnosed: potential for greatest benefit Ideal Profile for New Therapeutics indication unmet need
  15. 15. high indication unmet need low low Efficacy/Tolerability high 15 newly diagnosed Clinically/Commerically unacceptable
  16. 16. 16 high Unmet Need low low high Tolerability naive
  17. 17. 17 high Unmet Need low low high Tolerability Ist line
  18. 18. 18 high Unmet Need low low high Tolerability 2nd-3rd line
  19. 19. 19 high Unmet Need low low high Tolerability last - salvage
  20. 20. 20 high Unmet Need low low high Tolerability This is a typical early stage clinical trial population
  21. 21. 21 Efficacy v Tolerability: an old issue with rapidly evolving expectations  Chemo/irradiation • poor tolerability, potential for a high intial overall response rate (ORR) • rarely induces complete responses (CR); poor durability (DOR) • measurable impact on progression-free survival (PFS) • limited impact on median overall survival (med OS) • drives resistance  Targeted therapies (NCEs, mAbs) • variable tolerability • can induce a high ORR • some CRs; good PR rate • limited DOR • better PFS than chemo alone • can improve OS • drives resistance • some notable successes
  22. 22. 22 Efficacy v Tolerability: an old issue with rapidly evolving expectations  Immunotherapy – • low ORR, but... • CRs, PRs and SD with good DOR • Clear PFS and OS benefit, but let's look more closely... with immune checkpoint monotherapy this number can be low the long tail drags OS with it
  23. 23. 23 Efficacy/Tolerability: where we are headed depends on the indication  Hematologists have been excited about the "post-chemo" era. Why? Ibrutinib, rituxumab, idelalisib, revlimid etc ...  Solid tumor oncologists already know from targeted therapies that some of their patients can be cured (e.g. targeted therapies & antibodies in breast cancer) – anticipating better cure rates with IO  Oncologists in general are seeing success where for decades there has been only abject failure (NSCLC, H&N, bladder, etc)  All oncologists recognize the importance of being able to treat their elderly (or just beaten down) patients  In this landscape, the efficacy/tolerability profile can be differentiating
  24. 24. Next Gen Immuno-Oncology: Central Themes • what we want in specific indications:  better response rates  more durable responses  better tolerability • because we are addressing new benchmarks clinical practice is evolving quickly • for preclinical and early clinical programs a critical exercise is to look ahead in an effort to anticipate unmet need in a rapidly changing environment 24
  25. 25. The Big Three 25
  26. 26. Immunotherapeutics: CTLA-4 and PD-1 Lymph Node "inflammatory site (tumor)
  27. 27. Immunotherapeutics: CTLA4 Lymph Node • ipilimumab, IgG1 (BMS)  approved for refractory or advanced metastatic melanoma (Vervoytm)  Blocks CTLA4 from shutting down T cell activation  Likely blocks or depletes Tregs in the lymph node and the tumor • tremelimumab (Pfizer), in many trials, including with anti-PD-L1 (Medi4736; AZN)  Phase 3 monotherapy trial in advanced melanoma stopped in 2008 on futility 27
  28. 28. Immunotherapeutics: PD-1 "inflammatory site (tumor) • anti-PD-1 mAbs  nivolumab, IgG4 (Opdivotm, BMS)  pembrolizumab, IgG4 (Keytrudatm,Merck) • anti-PD-L1  MDPL3280A, IgG1 (Roche)  MEDI-4736, IgG1 (AZN) • These agents block the interaction of PD-L1 (expressed on tumor cells and Tregs) with PD-1 expressed on T effector cells 28
  29. 29. anti-PD-1 approvals Pembrolizumab (Keytruda) 1) Unresectable or metastatic melanoma who no longer respond to other treatments (September 2014) Pembrolizumab was granted accelerated approval Nivolumab (Opdivo) 1) Unresectable or metastatic melanoma who no longer respond to other treatments (December 2014). - breakthrough designation, priority review and orphan product designation - where treatments include Vervoy (ipilimumab) or, if BRAF V600 mutation positive, a BRAF inhibitor. 2) Advanced/metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy (March 2015)
  30. 30. Melanoma case study
  31. 31. Immunotherapy case study: melanoma 31 Historical treatment of stage III/IV non-resectable and/or metastatic disease (not segmented by mutation status) ORR med OS 1 yr survival dacarbazine, other chemo 10-15% 7-9 mo 26-36% high-dose IL-2 16%* 12 mo n/r • *A small number patients experience long-term survival. High-dose IL-2 regimen is not more widely used due to toxicity profile.  These IL-2 data supported the hypothesis that melanoma is an immune responsive cancer.
  32. 32. 32 Ipilimumab in resistant/advanced melanoma patients Phase 3, n= 676* ORR % med OS (months) 1 yr % survival % progressed ipilimumab 38** 10 45.6 59 ipi+gp100 20 10.1 43.6 51 gp100 15 6.4 25.3 65 * Hodi et al. 2010. NEJM 363: 711-723; **atypically high
  33. 33. Ipilimumab in treatment-naive melanoma 33 ORR % med OS (months) 1 yr % survival comparator data (prior slide) 20 10 45 ipilimumab 38 13.5 54 * Dummer et al. 2014. J. Transl. Med. 12(Suppl 1):P8. post-hoc analysis of 4 trials* • moving to first line modestly improves outcome • stresses need for combination therapy • toxicity is a complicating issue, approved dose is 3mpg
  34. 34. Ipilimumab plus SOC 34 • ipilimumab plus dacarbazine in adv melanoma*  not better than ipilimumab alone at 1 year  higher dropout rate than monotherapy due to adverse events med OS 1 yr OS Gr 3/4 AEs combo 11.2 mo 47.3% 56.3% dacarbazine 9.1 mo 36.3% 27.5% * Robert et al. 2011 NEJM 364: 2517-2526
  35. 35. Ipilimumab and dacarbazine 35 prior treatment treatment 3 yr % survival 4 yr % survival 5 yr % survival* Phase 3 (trial '024) none ipi 10mpg plus dacarbazine 21.2 19 18.2 " none dacarbazine 12.1 9.6 8.8 Phase 2 ('007, '008, '022) none ipi 0.3, 3, 10 mpk - 38 - 49 38 - 49 " yes " - 14 - 28 12 - 28 longer term followup *JCO published online on February 23, 2015 (Wolchok) ESMO abstracts 2012
  36. 36. Toxicity is a complicating issue – why? 36 • biggest issue assocated with these toxicities is treatment discontinuation (drop-out), leaving patients with an unclear path forward. This has the effect of lowering therapy penetrance into the patient population. • anti-PD-1 pathway therapeutics already show better tolerability
  37. 37. Check-in: central themes • better response rates  response rate improved  we don't know which patients will respond, and this remains an issue for the front line setting • more durable responses  some durable responses are obtained  some responders can do remarkably well • better tolerability  better than chemo but toxicity may lead to discontinuation  tolerability is an evolving issue – still trumped by efficacy 37
  38. 38. Melanoma and PD-1 pathway inhibitors: nivolumab 38 ORR % med OS 1 yr survival % pts progressing % nivolumab in pre- treated patients, ipi-naive* 41 20.3 63 >55% nivolumab in untreated, BRAF wt patients** 40 not reached (follow-up up to 16.7 mo) 73 47 dacabazine control** 14 10.8 42 85 * Hodi, ASCO 2014; ** Robert et al NEJM Nov 2014
  39. 39. PD-1 pathway inhibitors: pembrolizumab 39Mahoney and Atkins, 2014 Oncology 28 Suppl 3:39-48 adv/met melanoma adv/met melanoma adv/met melanoma
  40. 40. PD-1 pathway inhibition resistant, ipi-refractory metastatic melanoma 40Mahoney and Atkins, 2014 Oncology 28 Suppl 3:39-48 ORR (2 diff doses) PFS 1 yr survival pembro 26-34% 34-38 58-72% chemo 4 16 26-35%
  41. 41. Nivolumab + ipilimumab combination 41Mahoney and Atkins, 2014 Oncology 28 Suppl 3:39-48 • 80% 1 year survival
  42. 42. Melanoma summary 42 ORR % med OS 1 yr survival % where we started 12 8 months 30 ipi/nivo combo 42 40 months 85 best comparator* 64 not reached** 72 * dabrafenib (BRAFi) + trametinib (MEKi) in BRAF V600E/K mutated melanoma; Robert et al. NEJM Nov 2014. ** median followup ~10 months
  43. 43. Comparative tox profiles - monotherapy 43Kim and Eder 2014 Oncology
  44. 44. 44 Tox profiles – combotherapy ipi/nivo • 21% of patients terminated treatment due to toxicity • toxicity is associated with positive clinical response • oncologists: the GI tox is very difficult and limits use Kim and Eder 2014 Oncology
  45. 45. 45 Tox profiles – BRAF/MEK combo • grade 3/4 AEs in 48% of pts • 3 pts died: 2 w/ cerebral hemorrhage and 1 w/ brainstem hemorrhage • new tumors (non- melanoma) developed in 3 pts • cardiac abnormalities in 8% • we'll have to wait for resistance data
  46. 46. Immunotherapy for melanoma: food for thought 46 • Resistance to ipilimumab therapy following radiotherapy includes upregulation of PD-L1 (Victor et al 2015. Nature, doi:10.1038/nature14292; also AACR15 abstract #2858) • Preclinically, anti-CTLA4 and anti-PD-1 therapeutics have been shown to augment neoantigen responses within TIL populations; this has important implications for adjacent fields (e.g vaccines) • BRAF inhibitors transiently release neoantigens that can expand T cell responses in the presence of immune checkpoint inhibition; conversely MEK inhibition may blunt T cell activation by direct effects on T cells (AACR15 Abstract #SY26-03) • The sequence in which combination therapies are applied has yet to be optimized – update here?
  47. 47. Immunotherapy in other indications 47
  48. 48. BMS declared IO pipeline (March 2015)
  49. 49. Ipililumab Phase 3 examples 49 indication combination comparator trial newly diagnosed adv melanoma nivolumab placebo CheckMate 067 NCT01844505 adv melanoma nivolumab; dabrafenib* (BRAFV600); trametinib (MEK) none, cross-over design by sequence NCT02224781 adv prostate - placebo NCT01057810 sq NSCLC + chemo chemo NCT02279732 adv/met RCC nivolumab sunitinib CheckMate 213 NCT02231749 ED-SCLC + chemo chemo NCT01450761 * Rx of melanoma w/1 mo run-in w/vemurafenib (BRAF V600E i) followed by ipilimumab caused grade 3 elevations in aminotransferase levels and concomitant grade 2/3 change in the total bilirubin level: liver toxicity sufficiently severe to cause study termination (Ribas et al. 2013. NEJM 368: 1365-1366)
  50. 50. Ipililumab: interesting combos 50 Radiation lung, liver anti-VEGF melanoma Radiosurgery melanoma lenalidomide adv cancers Chemo melanoma
  51. 51. Ipililumab combos continued 51 imatinib (TKI) adv cancers IL-21 melanoma an RTKi* renal radiation melanoma * Sunitinib blocks VEGF signaling and it's use is linked to elevated immune responses to solid tumors, notably RCC. But we have to be careful....a clinical trial of ipilimumab and sunitinib was halted abrupty due to acute renal failure
  52. 52. Nivolumab in the clinic: recent and ongoing trials 52 indication comparator trial Phase recurrent melanoma ipilimumab CheckMate 238 NCT02388906 3 Sq NSCLC - (multiple line failures) CheckMate 063 NCT01721759 2 stopped on efficacy Sq NSCLC docetaxel CheckMate 017 NCT01642004 3 stopped on efficacy adv/res NSCLC chemo (investigator's choice) CheckMate 026 NCT02041533 3 recurrent GBM bevacizumab (anti- VEGF) CheckMate 143 NCT02017717 3 adv/res Sq H&N cetuximab (anti- EGFR) +/- chemo CheckMate 141 NCT02105636 3 adv/res gastric cancer placebo NCT02267343 3
  53. 53. Nivolumab in the clinic: interesting combos 53 RTK* or ipilimumab met RCC Abraxane/Chemo adv solid tumors CELG anti-KIR heme malignancies kitchen sink NSCLC anti-VEGF mRCC
  54. 54. Nivolumab combos... 54 dasatinib (Bcr-Abl TKI) CML ibrutinib (BTKi) heme malignancies JNJ IDO adv cancers INCY, BMS ipilimumab adv solid tumors
  55. 55. Nivolumab combos...last page 55 anti-CD27 select adv cancers Celldex, BMS ipilimumab CNS melanoma dabrafenib +/- trametinib melanoma
  56. 56. Pembrolizumab in the clinic: Phase 3 and other select examples 56 indication combination or other comparator trial note met Sq H&N (1st line) chemo cetuximab (anti-EGFR) + chemo Keynote-048 NCT0235803 P3 PD-L1+ adv NSCLC - chemo Keynote-042 NCT02220894 P3 adv melanoma - ipilimumab Keynote-006 NCT01866319 P3 adv urothelial cancer - chemo Keynote-045 NCT02256436 P3 adv/res gastric adenoCa - paclitaxel Keynote-061 NCT02370498 P3 adv cancers response relative to tumor PD-L1+ - Keynote-001 NCT01295827 P1, NSCLC data at AACR15 #CT104 mesothelioma - - Keynote-028 NCT02054806 P1, data at AACR15 #CT103
  57. 57. Pembrolizumab: example combos 57 VEGFR1/2-Fc adv solid cancers post-chemoradiation NSCLC Abraxane NSCLC Merck, CELG chemoradiation pancreatic cancer RTKi (EGFR/Her2) NSCLC
  58. 58. Pembrolizumab – other indications 58 chemo CRC Merkel Cell HL and DLBCL bevacizumab (anti-VEGF) GBM
  59. 59. Pembrolizumab... a few others 59 pazopanib RCC BTKi (?) bladder Ca thymic Ca anti-4-1BB adv solid tumors
  60. 60. What does this landscape tell us? • the volume of clinical data will be enormous, difficult to absorb • immune checkpoint inhibitors to CTLA4, PD-1 and PD-L1 (see backup slides) are likely to become dominant background therapeutics in many indications • the penetrance of these therapeutics into diverse indications will depend on at least three distinct factors:  immune response profile of the specific indication and further, of that indication (tumor) in each specific patient (e.g, immunoscore)  mutational profile (oncogenic, antigenic) of the tumor(s) in each specific patient  efficacy/safety profile of the therapeutic in combination with SOC or novel therapeutics  the evolving competitive landscape - as an example, hematologic malignancies may be better served by other therapeutic modalities Novel therapeutics will need to fit into this landscape 60
  61. 61. A note on PD-L1 inhibition 61 • Anti-PD-L1 inhibitors have the gentlest tox profile of the class, albeit with less efficacy data behind them, so we'll see... • updates here? MEDI4736 (PD-L1) dabrafenib (BRAFi) trametinib (MEKi)
  62. 62. WHAT NEXT? 62
  63. 63. Novel Immunotherapies: Organizing Principals 63 Tumor cells Lymphocyte subsets Microenvironment
  64. 64. 64 which is what is wrong with this picture: • Diverse targets • Inhibitory and activating pathways • Known and unknown biologies • Static • Rationale required for targeting as mono- or combo-therapy absent How do you approach this complexity? Mahoney et al, NRDD in press This target list just keeps growing
  65. 65. 65 Organizing Principals – Deconstructing the landscape
  66. 66. 66Mahoney et al. NRDD, in press Activating pathways of the TNFRSF • Multiple antibodies in clinical development, none very far advanced • All appear relatively tolerable, once dose is established • Although diverse MOA are postulated within this group of receptors, it is unclear how much the biology will overlap or be affected by FcR-engagement
  67. 67. 67 4-1BB/CD137 • Co-stimulatory molecule on T cells and NK cells: ligation induces cell activation and enhances effector function • Abundant preclinical data support of combination studies with many other agents • Clearly capable of driving T cell expansion and memory as demonstrated (artificially) by the UPenn CAR T program • Early clinical PD data show expansion of T cell and NK cell subsets and clinical activity in melanoma, RCC, ovarian Ca (PR and sustained SD) • 4-1BB expression appears to accurately identify tumor reactive TIL in some tumor types, such as ovarian cancer* • On NK cells, FcR-engagement by therapeutic antibodies (rituximab, cetuximab, etc) strongly upregulates 4-1BB expression, opening the door for rational combinations** * Ye et al. 2014. Clin. Can. Res. 20: 44-55 ** Khort et al. 2014. JCI 124: 2668-2682
  68. 68. 68 Therapeutics targeting 4-1BB • Broad campaign by BMS to profile anti-4-1BB agonist activity of urelumab, an IgG4 agonist  monotherapy: solid tumors and Non-Hodgkin lymphoma (NHL)  rituximab combination for NHL  combination with elotuzumab (anti-CS-1 mAb) or lirilumab (anti-KIR mAb) for multiple myeloma  nivolumab combination in solid tumors and NHL  cetuximab (anti-EGFR mAb) in colorectal, Head and Neck carcinomas • Pfizer campaign with PF-05082566, an IgG2 agonist  monotherapy cohorts in melanoma and Merkel cell carcinoma and combination trials with rituximab in NHL  combination with pembrolizumab in solid tumors  The PFE/MRK deal will bring additional combos
  69. 69. 69 OX-40/CD134 • OX40L/OX40 pathway sustains the immune response during inflammation, i.e. during T cell activation, allowing T cell memory to develop • OX40 engagement can activate memory T cells as well and has diverse (mainly negative) effects on Tregs • Early clinical data showed a PD response that included increased numbers of circulating CD4+ T cells, CD8+ T cells and NK cells • OX40 plus 4-1BB agonist combination may drive an anti-tumor immune response by generating CD8+ T cell activity characterized by very high levels of IFN-g and granzyme B – the super CD8s We'll come back to look at CD27 in a bit...
  70. 70. 70Mahoney et al, NRDD, in press TCR, B7/CD28 and PD-L1/PD-1 clusters Novel targets: HHLA2 – TMIGD2 ICOS – agonist LAG3 – antagonist VISTA - ?
  71. 71. 71 HHLA2 • HHLA2 (aka B7H7/B7-H5/B7y): most closely related to butyrophilins • Putative ligand identified and an inhibitory role postulated • HHLA2 protein is widely expressed in human cancer*  breast, lung, thyroid, melanoma, pancreas, ovary, liver, bladder, colon, prostate, kidney, esophagus  In 50 patients with stage I-III TNBC, 56% of patients had high HHLA2 expression that was significantly associated with regional lymph node metastasis  low level normal expression on epithelial cells (gut, kidney, breast) • TCGA analysis showed that HHLA2 copy number gains were present in 29% of basal breast cancers • No clinical assets developed * Janakiram et al. Clin Can Res Dec 2014
  72. 72. 72 LAG3 • A CD4 homologue, LAG3 was shown to confer Treg function on transfected naive CD4+ T cells • LAG3 binds to the MHCII protein and is required (with CD4) for optimal T cell activation • LAG3 overexpression (e.g on anergic T cells and tumor cells) functions as a negative regulator of T cell response to MHCII-restricted antigen • Antagonism of both LAG3 and PD-1 can synergistically reactivated exhausted CD8+ T cells in mouse models • LAG3/PD-1 gene-deficient mice are highly competent to reject even poorly immunogenic tumors. • Several clinical agents in development, no data yet.
  73. 73. VISTA • Normally expressed on hematopoietic cells including myeloid cells and T cells • In multiple cancer models VISTA is found at particularly high levels on tumor-infiltrating myeloid cells • Appears to be a negative regulator of T cell responses, may suppress myeloid cell responses in the tumor microenvironment • Anti-VISTA antibody treatment blunts tumor development even in the presence of high PD-1 expression • Antibodies to VISTA are being developed by a private company, ImmuNext, in collaboration with Johnson&Johnson (JNJ) 73
  74. 74. Complicated targets 74
  75. 75. Complicated targets 75 Ceacam-1* Huang et al. 2015. Nature 517: 386-390 Ceacam-1* • Excellent preclinical data support targeting TIM-3, Ceacam1 and select components of the LIGHT/HVEM system • It seems likely that the clinic will teach us more about the activity of the HVEM and TIM-3 systems than we can learn from mouse modeling – the actual kinetics and function of pathway components in situ is likely to be critical to successful targeting
  76. 76. 76 • lets break away, and look more closely at specific cell types within the tumor microenvironment
  77. 77. 77 B7-H3/B7-H4: Poorly understood biology, B7-H3 is an ADC target Butyrophilins are widely expressed, ligands usually unknown, likely that new targets will be found here Aberrant and highly variable expression of TNFRs – ADC targets, CD30 also a CAR T target Mahoney et al, NRDD, in press Immune-modulatory proteins on tumor cells
  78. 78. 78Mahoney et al, NRDD, in press Immune-modulatory proteins on Tregs • Primary targets: inhibition overrules activation • Additional TNFRSF proteins: all of these are under preclinical and clinical investigation • VEGF receptors critical for cross-talk with stromal cells
  79. 79. 79 CD27, our third costimulatory TNFR • CD27 is constitutively expressed on most T effectors and a subset of NK cells • As postulated for 4-1BB and OX-40, CD27 is important for sustained T cell activity and the generation of T cell memory; indeed, CD27 is a marker of memory T cells; CD27 also drives the cytolytic activity of some NK cells • Celldex has developed varililumab, an anti-CD27 agonist antibody and arly clinical data from a Phase 1 dose trial in NHL and solid tumors demonstrated tolerability and some measureable clinical responses • Listed clinical trials include a combination with nivolumab in solid tumors Other critical pathways under active investigation:  CD40  GITR  TNFRSF25  DR5/TrailR2
  80. 80. 80Mahoney et al, NRDD, in press NK cells: the next wave of immune-modulators
  81. 81. 81 NK cells: the next wave of immune-modulators Watch list: KIRs (Innate Pharma) LIRs (ILTs) Siglecs The PVR/nectin family (TIGIT; Genentech) C-Type lectins (Innate Pharma)
  82. 82. 82 KIR-modulators • Killer inhibitory receptors fall into two subclasses,  the killer cell immunoglobulin-like receptors (KIRs)  C-type lectin transmembrane receptors (eg. NKG families) • KIR function is regulated through interaction with cell surface HLA proteins that transduce an inhibitory signal to NK cells. • lirilumab is an antagonist antibody that binds to the KIR2DL1,2,3 receptors to prevent their inhibitory signaling and increasing NK cell– mediated killing of HLA-C–expressing tumor cells. • In a Phase I monotherapy trial in acute myeloid leukemia (AML) IPH2101/lirilumab had only modest toxicity (grades 1-2) and showed signs of clinical activity • A Phase II study of lirilumab in AML is in progress
  83. 83. 83 BMS doubles-down with Innate's mAb • Innate Pharma and BMS are collaborating to develop lirilumab. • Combination Phase 1 trials of lirilumab in combination with nivolumab and ipilimumab for solid tumors have begun and a combination trial with elotuzumab (depleting anti-CS1 antibody from BMS and AbbVie) is underway for multiple myeloma. • A recent update to clinical trial filings indicates that BMS is adding lirilumab combinations with nivolumab to clinical trials of ipilimumab/nivolumab combos for hematological malignancies (next slide) • These updates are suggestive of broad utility of engaging NK cell activity • Innate is also developing an anti-MICA antibody to block inhibition mediated by MICA/NKG2D interaction, and they have an NKG2A program. Both are quite early.
  84. 84. 84 Lirilumab clinical trials: focus on heme malignancies
  85. 85. 85 TIGIT • TIGIT is a relatively new IgSF protein, with clear cell inhibitory function. • Defined binding to PVR and Nectin-2, potentially leading the way to influencing both T cells and NK cells through inhibition of this pathway • However, proteins in the nectin family may have diverse binding partners, complicating development, e.g. the TIGIT ligands may also bind DNAM and other PVRs • Genentech has developed TIGIT-specific therapeutics and recently showed that co-blockade of TIGIT and PD-L1 resulted in tumor rejection by restoring the function of exhausted tumor-infiltrating CD8+ T cells; however high concentration of ADCC-competent antibody was used, complicating interpretation* • Regardless, targeting TIGIT may be especially beneficial in tumor settings where both T cells and NK cells have therapeutic potential johnston et al. 2014. Cancer Cell
  86. 86. 86Mahoney et al, NRDD, in press Tumor microenvironment the new frontier, a wealth of targets
  87. 87. 87 IDO1 Indoleamine 2,3-dioxygenase (IDO1) is the rate-limiting enzyme for the catabolism cellular tryptophan. High levels of IDO1 reduce tryptophan levels and create bioactive tryptophan metabolites, a highly immunosuppressive combination In the tumor microenvironment IDO is produced by tumor cells and by tumor associated MDSC and tumor-associated macrophages (TAM) in response to inflammatory signals (IL-10, IFNy)  Incyte's IDO1 inhibitor INCB024360 is in Phase 1 & 2 clinical trials for metastatic melanoma in combination with ipilimumab and as monotherapy for ovarian cancer.  In the ipilimumab combination study, many patients demonstrated an objective response and maintained stable disease  Other studies include a Phase 1/2 study in advanced/metastatic cancers including melanoma and NSCLC in combination with pembrolizumab, nivolumab, MPDL3280A and MEDI4736 – the benefit of multiple collaborations  Newlink and Flexus deals highlight the intense interest in this target
  88. 88. 88 TGFb • Diverse methods have been employed in attempts to safely block TGFb activity, one of the most potent immunosuppressive growth factors • Among many other activities, TGFb stimulates expression and phosphorylation of IDO. This triggers additional signaling to allow paracrine (and chronic) expression of both TGFβ and IDO1 • Current therapeutics target activating integrins, e.g. avb6 or the GPCRs that are responsible for activating the integrins (e.g. LPA, other GPCRs) • LY2157299/galunisertib is a small-molecule kinase inhibitor from Eli Lilly designed to selectively block TGFb receptor signaling • Galunisertib has a well-defined therapeutic window based on reducing receptor signaling and has shown clinical activity in a variety of solid tumor models • Successful (safe) targeting of TGFb will be a stunning advance
  89. 89. 89 Adenosine A2aR is expressed on CD8+ TIL, NK cells and MDSC and is an important component of immune regulation, helping to stop immune responses in the context of inflammation Adenosine is produced by the nucleotidases CD39, an ATP/ADPase, and CD73, an AMPase. Both nucleotidases can be upregulated on tumor cells and also on tumor-associated Treg A proof of concept study using a substrate analog inhibitor of CD73 demonstrated additive anti-tumor activity with anti-CTLA4 antibody treatment in a melanoma model An anti-CD73 antibody had additive activity when combined with anti-CTLA4 or anti-PD-1 antibodies in multiple tumor models
  90. 90. 90 adenosine ... This study demonstrated particularly strong additive activity in the setting of anti-PD-1 therapy, possibly because adenosine upregulated PD-1 expression on the target tumor cells. These two studies focused on the effect of adenosine production and signaling through A2aR on CD8+ T cells. Emerging data suggest that A2aR signaling also triggers MDSC to promote immunosuppression, and that NK cells are negatively regulated via this pathway
  91. 91. • Checkpoints  CTLA4 and PD-1/L-1: crowded, little room for differentiation although top tier assets are still being sought – not every antibody is a success (see pidilizumab)  TIM-3, LAG-3: multiple programs underway at large pharma (NVS) and many small biotechs  Enough deals have been done that some sub-par assets are sitting on the shelf • Novel Pathways  What are these? everyone wants one...  Drives steep valuations (e.g. NLNK, Flexus) How can drug discovery navigate this landscape 91
  92. 92. • Vaccines  High value accrues to some programs, but the rules for success are unknown  Biggest issue: high risk – vaccines fails in Phase 3! • Immuno-stimulatory Pathways  4-1BB, GITR, OX40 illustrate the tortuous development pathways these assets can take  Some legacy anti-TNFRs signal non-physiologically  There is room for novel constructs like bispecifics  There are many novel pathways that are under- represented How can drug discovery navigate this landscape 92
  93. 93. • The optimal efficacy/tolerability paradigm will impact more and more indications as therapeutics are successful • Niche indications with high unmet need allow access to this remarkably competitive landscape • Novel interrogation points to drive diffferentiation:  T cells: effectors and Tregs  NK cells  The tumor microenvironment  The tumor itself Moving ahead 93
  94. 94. Novel Therapeutics: Organizing Principals 94 Tumor cells Lymphocyte subsets Microenvironment • TNFRSF proteins • KIRs • C-type lectins • TGFb • IDO-1 • Chemokine receptors • LAG3 • HHLA2 • TIM-3
  95. 95. 95 On Twitter @PDRennert LinkedIn/paulrennert
  96. 96. 96 BACKUPs on PD-L1 antagonists
  97. 97. Medi4736 in the clinic 97
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  103. 103. MPDL3280a in the clinic 103
  104. 104. MPDL3280a in the clinic 104
  105. 105. MPDL3280a in the clinic 105
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