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Topics neo-antigens vs shared antigens as targets for vaccines - - PDF document

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3/5/2018 The Evolving Role of Cancer Vaccines COL (ret) George E Peoples, MD, FACS Topics neo-antigens vs shared antigens as targets for vaccines new clinical settings (hence endpoints) for vaccine trials vaccines to improve

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SLIDE 1

3/5/2018 1

The Evolving Role

  • f Cancer Vaccines

COL (ret) George E Peoples, MD, FACS

  • neo-antigens vs shared antigens as targets for

vaccines

  • new clinical settings (hence endpoints) for

vaccine trials

  • vaccines to improve CPIs range of clinical

activity

  • new combinations (to include but not limited to

CPIs) to improve the outcomes in vaccine trials

  • address recent failed vaccine trials

Topics

  • Adjuvant setting is an appropriate

place to test vaccines

  • Combination therapies may be

even more effective

  • CPI + vaccines for the metastatic

setting

Conclusions

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SLIDE 2

3/5/2018 2

Vaccines for Solid Tumors

  • Hypothesis:

Cancer vaccines will be more effective in a minimal disease (adjuvant) setting

Adjuvant Setting – Why?

  • Vaccinate during disease-free interval

– Healthier immune system – Build up anti-tumor immunity

  • Single tumor cells/micromets
  • Theoretically

– Less tumor-related immune suppression – Fewer immune escape mechanisms – Less tumor microenvironment

  • Using vaccines as preventive agents

Adjuvant Setting – Challenges

  • Disease-free survival endpoint

– 2-3 yrs to endpoint

  • Based on recurrence rates

– May require large reductions in RRR – Or large treatment groups

  • Large studies that take a long time =

expensive

  • Difficult first step to prove efficacy of

vaccine technology

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SLIDE 3

3/5/2018 3

Proof of Concept in Phase III

  • Colon cancer

– OncoVax = autologous tumor + BCG – Stage II/III resected (four trials with >700 pts) – DFS/OS advantage in stage II

  • Lung cancer

– Stimuvax = MUC1 polypeptide – Stage III NSCLC treated with concurrent chemorads (n=1239, 806 pt subset) – Improved PFS/OS

  • Melanoma

– Melacine = allogeneic tumor cell lysates – Stage III resected (n=689 pts) – OS advantage in HLA-A2+ and HLA-Cw3+ pts

Proof of Efficacy (n=>1500 pts)

  • Breast cancer

– AE37 (ph2 = 301 pts) – GP2 (ph2 = 180 pts) – NeuVax (ph2 = 195 pts, ph3 = 760 pts)

  • Ovarian cancer

– FBP (ph1/2a = 51 pts)

  • Melanoma

– TLPLDC (ph2b = 120 pts) – TLPO (ph2b = 60 pts) (ongoing)

HER2

ECD TMD ICD

Extracellular Domain (aa 1-652) Intracellular Domain (aa 676-1255) Trans Membrane Domain (aa 653-675) E75-peptide vaccine (aa 369-377) MHC Class I : HLA-A2 & HLA-A3 Stimulate CD8 T cells

K I F G S L A F L

GP2-peptide vaccine (aa 654-662) MHC Class I : HLA-A2 Stimulate CD8 T cells

I I S A VV G I L

AE37-peptide vaccine (aa 776-790) MHC Class II : multi-allele Stimulate CD4 T cells

G V G S P Y V S R L L G I C L

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SLIDE 4

3/5/2018 4

AE37/GP2 Phase II Trial

S T R A T I F Y R A N D O M I Z E

AE37+GM GM only

Specific Aims

1. Recurrence 2. Time to Recurrence 3. Immunologic response correlation S T R A T I F Y R A N D O M I Z E

GM only GP2+GM

A2- A2+

  • NP or high-

risk NN

  • HER2 IHC

1+, 2+ or 3+

  • NED after

SOC therapy

AE37/GP2 Phase II Trial Primary Analysis: GP2

Mittendorf EA et al, Oncotarget 2016;7(40):66192-66201

37% RRR

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SLIDE 5

3/5/2018 5

Primary Analysis: AE37

40% RRR

Mittendorf EA, et al. Ann Oncol 2016;27(7):1241-8.

60% RRR

HER2 1+/2+ TNBC

HER2

ECD TMD ICD

Extracellular Domain (aa 1-652) Intracellular Domain (aa 676-1255) Trans Membrane Domain (aa 653-675) E75-peptide vaccine (aa 369-377) MHC Class I : HLA-A2 & HLA-A3 Stimulate CD8+ T cells

K I F G S L A F L

GP2-peptide vaccine (aa 654-662) MHC Class I : HLA-A2 Stimulate CD8 + T cells

I I S A VV G I L

AE37-peptide vaccine (aa 776-790) MHC Class II : multi-allele Stimulate CD4 + T cells

G V G S P Y V S R L L G I C L

E75 Phase II – 5 yr DFS

  • Mittendorf EA et al. Ann Oncol 2014;25(9):1735-42.

89.7% Vaccinated (n=108) Control (n=79) 80.2% Fraction Surviving Disease Free Time (months) P=.08

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SLIDE 6

3/5/2018 6

DFS – Optimal Dosing

Mittendorf EA et al. Ann Oncol 2014;25(9):1735-42

Optimally dosed (n=37) Suboptimally dosed (n=71) Control (n=79) 80.2% 94.6% 87.1% Fraction Surviving Disease Free Time (months) P=.05*

Study Population Adjuvant Breast cancer (BC) patients, n=700, randomized 1:1

  • Node positive (NP),

HLA A2/A3+, low and intermediate HER2 expression

  • Achieve CR with

standard of care (SOC)

  • Stratified by Stage (IIA-

IIIA), Type of Surgery, Hormone Receptor and Menopausal status

  • Single dose level of

GM-CSF +/- E75

1 2 3 4 Interim analysis by DSMB at n=70 events Endpoint DFS at n=139 events/36 mos. E75 + GM-CSF + GM-CSF Placebo Dosing by Month + 1 booster dose every 6 months thereafter + Dosing to disease progression or 36 months 5 6

Phase III Study Schema: PRESENT (Prevention of Recurrence in Early Stage Node-Positive Breast Cancer with Low to Intermediate HER2 Expression with NeuVax Treatment

PI: E.A. Mittendorf

PRESENT Trial Results

  • N=758

– 376 VG vs 382 CG – well matched

  • 71 events triggered interim

– recurrences, deaths, second cancers

  • mandatory annual scans
  • new radiographic findings (no bx, serial images, f/u)

– Recurrences - VG > CG

  • same number of deaths, second ca, clinical recurrences
  • 3x the # of new radiographic findings in VG c/w CG
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SLIDE 7

3/5/2018 7

Proof of Efficacy (n=>1500 pts)

  • Breast cancer

– AE37 (ph2 = 301 pts) – GP2 (ph2 = 180 pts) – NeuVax (ph2 = 195 pts, ph3 = 760 pts)

  • Ovarian cancer

– FBP (ph1/2a = 51 pts)

  • Melanoma

– TLPLDC (ph2b = 120 pts) – TLPO (ph2b = 60 pts) (ongoing)

Interim Analysis: E39 Interim Analysis: E39

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SLIDE 8

3/5/2018 8

  • Adjuvant setting is an appropriate

place to test vaccines

– Hale DF, Vreeland TJ, Peoples GE. Arming the Immune System Through Vaccination to Prevent Cancer Recurrence. Am Soc Clin Oncol Educ Book. 2016;35:e159-67.

  • Combination therapies may be

even more effective

  • CPI + vaccines for the metastatic

setting

Conclusions

  • Adjuvant setting is an appropriate

place to test vaccines

– Hale DF, Vreeland TJ, Peoples GE. Arming the Immune System Through Vaccination to Prevent Cancer Recurrence. Am Soc Clin Oncol Educ Book. 2016;35:e159-67.

  • Combination therapies may be

even more effective

  • CPI + vaccines for the metastatic

setting

Conclusions Combination Immunotherapy

  • E75 and GP2 trials

–N = 89 patients with HER2 3+ breast cancer that received trastuzumab

  • 55 vaccinated
  • 34 unvaccinated controls
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SLIDE 9

3/5/2018 9

Combination Immunotherapy

Median f/u = 36 months 100% 84%

Phase II: NeuVax (E75) + Herceptin v. Herceptin alone in HER2 IHC 1+/2+, early-stage breast cancer

Study Population Adjuvant Breast cancer (BC) patients, n=300, randomized 1:1

  • HLA A2/A3+, low and

intermediate HER2 (IHC 1+/2+) expression; node positive (HR+/-) or node negative (HR-)

  • Stratified by nodal

status and HER2 status

  • Single dose level of

Herceptin + NeuVax vs Herceptin + GM- CSF alone

Primary Endpoint DFS at 24 mos.

NeuVax (E75) + Herceptin Herceptin

Standard Herceptin dosing every 3 weeks for 1 year + 1 booster dose every 6 months thereafter + Dosing to disease progression

  • r 36 months

6 doses of NeuVax given every 3 weeks starting with third dose of Herceptin Secondary Endpoint DFS at 36 mos.

E75 + trastuzumab Trials

  • In HER2 1-2+ trial

– PI: Jarrod Holmes – 32 sites – Enrolled 284/300 pts (randomized 253)

  • Interim safety analysis

– No SAEs, min related AEs – No increase in cardiotoxicity assoc with trastuzumab

  • Efficacy at 2 and 3 yrs
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SLIDE 10

3/5/2018 10

E75 + trastuzumab Trials

  • In HER2 3+ trial

– PI: Beth Mittendorf – 21 sites – Enrolled 77/100 pts (randomized 68)

  • Interim safety analysis

– No SAEs, min related AEs – No increase in cardiotoxicity assoc with trastuzumab

  • Efficacy at 3 yrs
  • Adjuvant setting is an appropriate

place to test vaccines

  • Combination therapies may be

even more effective

  • CPI + vaccines for the metastatic

setting

Conclusions

  • Rationale

– CPI highly effective in a minority of pts – Less effective in tumors lacking infiltrating T cells – Vaccines induce tumor-reactive CTL

  • Metastatic setting

– Tumor microenvironment known to be suppressive to tumor- reactive T cells – Vaccines largely ineffective in the metastatic setting

  • Therefore,

– Vaccines can increase the number of tumor-reactive T cells for CPI – CPI can protect tumor-reactive T cells in the tumor microenvironment

Vaccines + CPI

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SLIDE 11

3/5/2018 11

  • Vreeland TJ, Clifton GT, Herbert GS, Hale DF, Jackson DO,

Berry JS, Peoples GE. Gaining ground on a cure through synergy: combining checkpoint inhibitors with cancer vaccines. Expert Rev Clin Immunol 2016 Dec;12(12):1347-1357.

  • 19 trials, 14 vaccines, 7 disease types
  • 5 checkpoint modulators

– ipilimumab – nivolumab – pembrolizumab – atezolizumab – Indoximod

Vaccines + CPI Phase II Trials VADIS (Vaccine in DCIS)

  • Led by the NCI and MDACC
  • PI: Beth Mittendorf
  • N=40 pts, randomized 2:1
  • Neoadjuvant vaccination with E75 + GM-

CSF vs GM alone

  • Endpoints

– TIL by HE/IHC – E75-specific CTL – Pathologic changes in the tumor

Vaccination in DCIS

  • Vaccines may be most effective in

DCIS:

  • Before tumor cells are genetically unstable and

rapidly dividing

  • When patients are not immunosuppressed
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SLIDE 12

3/5/2018 12

DC Vaccine in DCIS

  • ↑ antigen specific,

IFN-γ secreting CD4+ and CD8+ T cells

  • Accumulation of T

cells and B cells in breast

  • Induction of

complement- dependent, tumor- lytic antibodies

CD4 CD8 Pre- Vaccination Post- Vaccination

Czerniecki BJ et al. Cancer Res 2007;67(4):1842-1852

Where to now?

Secondary prevention Combination immunotherapy with Trastuzumab Combination immunotherapy with checkpoint blockade Neoadjuvant trials Primary Prevention