Follicular Lymphoma: Updates and novel immune therapies

Transcription

1 Follicular Lymphoma: Updates and novel immune therapies Larry W. Kwak, M.D., Ph.D. Cancer Center Associate Director for Translational Research and Developmental Therapeutics Director, Toni Stephenson Lymphoma Center Dr. Michael Friedman Professor for Translational Medicine

2 DISCLOSURES I am a consultant for Xeme Biopharma, Celltrion & Sellas Biotechnologies and a stock shareholder with Xeme Biopharma.

3 Follicular NHL 2nd most common NHL 22,000 new cases/yr, median age 60 Normal counterpart germinal center B cell Graded by # large cells Grade I, II, IIIa indolent Gr IIIb aggressive (Gr IIIb DLBCL)

4 Pathogenesis of follicular lymphoma t(14;18)

5 Natural history of follicular NHL Spontaneous remissions occur Waxing and waning disease Survive for years without Rx Transformation to aggressive NHL - 1-4% per year

6 Usual Clinical presentation Painless lymphadenopathy, waxing and waning B symptoms uncommon Abdominal, retroperitoneal masses Spleen involved (40%) Marrow frequently involved (>70%) Extranodal sites (except the marrow) uncommon. Elevated LDH uncommon Stage III/IV in over 80% of patients

7 Prognosis in follicular NHL - FLIPI 4167 patients Age > 60, Stage III/IV, > 4 nodal sites, LDH, Hgb < 12 Low risk 0-1 Intermediate risk 2 High risk 3-5 FLIPI2: B2M, BM involvement, LN > 6cm

8 Follicular Lymphoma International Prognostic Index (FLIPI) >3

9 Why treat follicular NHL? Local symptoms due to progressive or bulky nodal disease. Compromised organ function due to progressive or bulky disease. B symptoms. Symptomatic extranodal disease, effusions. Cytopenias (BM infiltration, hypersplenism).

10 Treatment Principles Early treatment not beneficial. Anthracyclines not clearly beneficial (CHOP not better bendamustine). Remissions progressively shorten. Chemotherapy + anti-cd20 monoclonal antibody therapy (rituximab) has had an impact on BOTH remission duration and survival.

11 Watch and Wait Strategy Overall survival Time to first therapy

12 Early Stage Follicular Lymphoma 24 Gy IFRT is a potentially curative approach 10-yr PFS/OS: 45-60%/60-80% Median survival years

13 Rituximab Since 1998, important addition to treatment armamentarium. Chimeric anti-cd20 B cell monoclonal antibody. Triggers multiple cell-damaging mechanisms. Difficult in vivo to differentiate these various mechanisms in humans.

14 Mechanism of Action of Tumor Targeting mab Kasi, et al. Critical Care. 2012;16:231.

15 Rituximab as initial treatment Initial therapy 72% RR, 36% CR Response improves over time Median time to progression 2.2 y Witzig et al, JCO 23:1103, 2005

16 Bendamustine-Rituximab (B-R) vs CHOP-R StiL NHL Bendamustine-Rituximab Follicular Waldenströms Marginal zone Small lymphocytic Mantle cell R CHOP-Rituximab Bendamustine 90 mg/m 2 day R day 1, max 6 cycles, q 4 wks. CHOP-R, max 6 cycles, q 3 wks.

17 Bendamustine-R v CHOP-R follicular lymphoma PFS No difference in overall survival BR less toxic than CHOP-R

18 Chemotherapy + rituximab followed by maintenance or observation (PRIMA trial) PFS OS

19 Newly Diagnosed, Follicular Lymphoma Stage I, II (non-bulky) YES XRT feasible? NO IFRT alone (24 Gy) (Gr 1-2) R-CHOP x 3 cycles + IFRT (24-30 Gy) (Gr 3A/B) Gr 1-2: R-bendamustine x 6 cycles Gr 3A/B: R-CHOP x 6 cycles City of Hope - Standard of Care 2016

20 Newly Diagnosed, Advanced Stage Follicular Lymphoma (III, IV, Stage II bulky) NO Treatment indicated? YES Observation Rituximab alone +/- maintenance R-bendamustine x 6 cycles R-CHOP +/- maintenance (Grade 3A/B) City of Hope - Standard of Care 2016

21 Relapsed or Refractory Follicular Lymphoma NO low risk/durable response to prior rituximab monotherapy? YES 1. Clinical trial 2. R-CHOP or R-bendamustine (depending on upfront tx) 3. Lenalidomide + rituximab 4. Idelalisib (failed 2 lines) 5. Stem cell transplantation (refractory) Rituximab alone NO Response? YES Consider maintenance City of Hope - Standard of Care 2016

22 Novel Therapies Molecularly targeted bcl-2, B cell kinases (syk, btk, PI3K) New monoclonal antibodies humanized, different targets Novel immunotherapies PD-1/PD-L1 inhibition Vaccines

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24 Major immunotherapy strategies Checkpoint blockade with specific mab Anti-CTLA4 * Anti-PD1 * Adoptive transfer of humant cells - Chimeric antigen receptor transduced (CARs) - T-cell receptor transduced Cancer vaccines * FDA approved

25 Pidilizumab (anti-pd1) + rituximab in relapsed follicular lymphoma (FL) patients Rituximab Days Pidilizumab If SD/PR/CR continue 8 more infusions every 4 wks n = 30 Days CT/PET/BM q3mo Core Bx Blood/PBMC 1,2 14 Pidilizumab (CT-011) iv infusion at 3.0 mg/kg/cycle q4 weeks for up to 12 cycles Rituximab - iv infusion at a dose of 375 mg/m 2 weekly for 4 weeks

26 Pidilizumab + Rituximab Best response

27 Summary of clinical results Pidilizumab + Rituximab therapy is well tolerated, there were no grade/4 or autoimmune adverse events noted. Highly effective in relapsed, rituximab-sensitive follicular lymphoma with an ORR of 66% and CR of 52% Compares favorably to previous rituximab retreatment data (e.g. ORR of 40% & CR of 11% - Davis et al, J Clin Oncol 2000) Westin et al. [Neelapu, Kwak] Lancet Oncol, 2014

28 41-gene signature in pretreatment tumor biopsies correlated with PFS 41-genes more highly expressed in effector (Th1 antitumor) vs. follicular helper T cells (T FH pro-tumor) Signature average Dichotomization PFS according to 41-gene signature P=0.004 N = 18 patients

29 Summary of laboratory correlative studies Patients with high expression of the 41-gene signature suggesting more Th1 vs. T fh in the tumor and therefore, a pre-existing antitumor immune response had better response and PFS. If confirmed in larger trials, the 41-gene signature may offer a predictive biomarker for selection of patients for treatment with this class of agents in FL (signature not predictive in external dataset of 191 patients) Pidilizumab therapy was associated with increase in the numbers of effector and central memory CD4 + T cells and activation of NK cells in the tumor microenvironment and peripheral blood (not shown). Westin et al. [Neelapu, Kwak] Lancet Oncol, 2014

30 Positive controlled Phase III cancer vaccine clinical trials Sipuleucel-T (prostate cancer) * NEJM July 2010 gp100 peptide (melanoma) NEJM June 2011 B-cell idiotype protein (lymphoma) J Clin Oncol July 2011 * FDA approved

31 Bench-to-bedside development of a homegrown therapeutic agent from an academic laboratory Cancer vaccine strategy Y Lymphoma Tumor Preclinical Addition of GM-CSF Adjuvant improves vaccine potency Phase I/II Clinical Trial (Nat Med 1999): Vaccine induces molecular remissions (Proc Natl Acad Sci 1996) Idiotype protein Phase III Controlled Clinical Trial (J Clin Oncol 2011) Vaccine prolongs DFS in patients in a chemotherapy-induced remission (n=117, p=0.045) CD8+

32 Conclusions: Id protein vaccine Phase III trial As a controlled clinical experiment, the positive lymphoma vaccine Phase IIII randomized trial has scientific value for its validation of the cancer vaccine concept (improved disease-free survival in 1st remission patients) Long-term clinical experience with the vaccine demonstrates low toxicity, making it ideal for consolidation or maintenance therapy (standard of care) Additional clinical trials are needed, combining this vaccine with anti-cd20 mab (rituximab)-containing chemotherapy regimens in the U.S.

33 2 nd generation DNA Vaccine Strategy Maintain or improve efficacy Reduce Manufacturing Time For Protein Vaccines: 3-6 months For DNA Vaccines: 4-5 weeks

34 Next generation vaccines: targeting dendritic cells with genetic fusions Antigen Presenting Cell (APC) Receptor Targeting Biragyn et al. [Kwak] Nature Biotech 1999; Science 2002

35 Second step First step VH1/2 VH 3 VH 4/5 VH6 Actin Vk1/2 Vk3 Vk4 Personalized identification of lymphoma-associated V H/L gene from patient biopsy BM Total RNA cdna Touch down semi-qpcr Determine lymphoma associated VH/VL gene scfc gene synthesis Slide courtesy of Dr. Soung-Chul Cha Isolation fragment Clone Transformation Pick random colonies DNA sequencing Clone into DNA vaccine plasmid origin: National Gene Vector Laboratory (licensed to Aldevron)

36 Phase I Study of an Active Immunotherapy for Asymptomatic Phase Lymphoplasmacytic Lymphoma with DNA Vaccines Encoding Antigen-Chemokine Fusion (activated March 2015) Formulation and Administration: 0.5ml intramuscular injection rotated between thighs Dosing Cohorts: Cohort 1: 500 g Cohort 2: 2500 g Schedule of Administration: Wk 0 Wk 4 Wk 8 Multiple Myeloma SPORE (P50 CA142509) Project 2 (Neelapu/Thomas)

37 Future development of other personalized cancer vaccines Vonderheide RH Nature Med 19:1098, 2013)

38 Future directions: Cancer vaccines Precision medicine approaches (genetic sequencing) to generate personalized vaccines Additional improvements in the vaccine delivery platforms (e.g. 2 nd generation idiotype DNA fusion vaccines) Combine lymphoma vaccines with strategies for checkpoint blockade

39 Acknowledgements Kwak Laboratory Hong Qin Soung-Chul Cha James Weng Ippei Sakamaki Guowei Wei Zhenyuan Dong Sheetal Rao Damian Gwak Sung Doo Kim Wesley Cheng Collaborators: MD Anderson Cancer Center Willem W. Overwijk Sattva Neelapu (lymphoma tissue bank) Sheeba Thomas Sapna Parshottam Karen C. Dwyer Roza Nurieva Yared Hailemichael Grant Funding Leukemia & Lymphoma Society (Quest for Cures ) NCI Myeloma SPORE (P50 CA142509) NCI Lymphoma SPORE (P50 CA136411)