Immunotherapy for cancer
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The document discusses cancer immunotherapy, highlighting its main approaches, including active immunization (cancer vaccines), adoptive cell transfer (e.g., CAR T-cells), and non-specific immune stimulation. It focuses on pembrolizumab and its effectiveness as a checkpoint inhibitor, detailing studies and survival rates, as well as associated adverse events. The document underscores the potential of immunotherapy to enhance immune system responses against cancer while emphasizing the importance of further research for patient selection.
Immunotherapy for cancer
- 1. Immunotherapy: New Standard for Treating Cancers Mary Ondinee M. Igot, MD, MSCM, FPCP, FPSMO Medical Oncologist / Neuro – Oncologist Asian Hospital and Medical Center
- 2. Outline • Main Approaches to Cancer Immunotherapy • The Anti-PDL1 Hype: Practice Changing Data • Indications for giving Pembrolizumab • Adverse events from Pembrolizumab
- 3. The Immune System and Cancer http://www.oxfordimmunotec.com/international/science/technology-2/
- 4. The Immune System and Cancer http://www.oxfordimmunotec.com/international/science/technology-2/ Monoclonal Antibodies 1. Rituximab (anti-CD20) 2. Trastuzumab (anti-HER2-neu) 3. Cetuximab (anti-EGFR) 4. Panitumumab (anti-EGFR) 5. Bevacizumab (anti-VEGF) 6. Ramucirumab (anti-VEGFR2) INTERFERE WITH GROWTH SIGNALS rather than by direct destruction of tumor cells
- 5. Immunotherapy Goals of immunotherapy: 1. Aid in the recognition of cancer as foreign by the immune system 2. Stimulate immune responsiveness 3. Relieve inhibition of the immune system that allows tolerance of tumor growth Differs from: • Chemotherapy : targets rapidly dividing cells • Targeted Therapies : interfere with key molecular events in tumor cells that drive tumor growth and invasion
- 6. Three Main Approaches to Cancer Immunotherapy http://www.oxfordimmunotec.com/international/science/technology-2/
- 7. Three Main Approaches to Cancer Immunotherapy http://www.oxfordimmunotec.com/international/science/technology-2/ I. Active immunization to enhance anti- tumor reactions (cancer vaccines)
- 9. Three Main Approaches to Cancer Immunotherapy http://www.oxfordimmunotec.com/international/science/technology-2/ I. Active immunization to enhance anti- tumor reactions (cancer vaccines) II. Passively transfer activated immune cells with anti-tumor activity (adoptive cell transfer >> CAR T-cells)
- 10. Chimeric antigen receptor (CAR) T cell therapy
- 11. • A patient with recurrent multifocal glioblastoma (brain and spine) received multiple infusions CAR T-cells over 220 days through 2 intracranial routes (resected tumor cavity and ventricular system). • After the treatment, regression of all the intracranial and spinal tumors were observed and the response continued for 7.5 months after the initiation of CAR T-cell therapy.
- 12. Three Main Approaches to Cancer Immunotherapy http://www.oxfordimmunotec.com/international/science/technology-2/ I. Active immunization to enhance anti- tumor reactions (cancer vaccines) II. Passively transfer activated immune cells with anti-tumor activity (adoptive immunity) III. Non-specific stimulation of immune reactions a. Stimulate effector cells i. IL-2 (melanoma, renal cell)
- 13. Interleukin-2 • Soluble T-cell growth factor • Received FDA approvals • 1992: metastatic renal cell carcinoma • 1998: metastatic melanoma • Both of these malignancies had some complete responders • Only recommended for high volume centers with extensive experience in its administraton T-cells secrete IL-2 necessary for the proliferation of T-cells.
- 14. Three Main Approaches to Cancer Immunotherapy http://www.oxfordimmunotec.com/international/science/technology-2/ I. Active immunization to enhance anti- tumor reactions (cancer vaccines) II. Passively transfer activated immune cells with anti-tumor activity (adoptive immunity) III. Non-specific stimulation of immune reactions a. Stimulate effector cells i. IL-2 (melanoma, renal cell) b. Inhibit regulatory factors i. Anti-CTLA4 ii. Anti-PD1 / Anti-PDL1
- 15. Immune checkpoints: CTLA-4 and PD-1/PD-L1 De Vita, 10th edition PD-1 or CTLA-4 engagement with its ligand, lead to T-cell inactivation Reduced cytokine production Reduces proliferation of T cells REDUCED KILLING OF CANCER CELLS by cytotoxic T cells == IMMUNOSTAT ==
- 16. Immunostat T-cell just stands by the cancer cell … instead of acting against it
- 17. • N = 676 previously treated Stage unresectable III/IV, randomized in a 3:1:1 to receive ipilimumab + gp100 vs gp100 vs ipilimumab alone • Median OS with ipilimumab alone was 10.1 months (HR for death in the comparison with gp100 alone, 0.66; P=0.003). • No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). NEJM 2010; 363; 711-723
- 19. 2015: Era of PD-1 inhibitors (Nivolumab and Pembrolizumab) …. what most of us refer to as IMMUNOTHERAPY
- 21. NEJM 2015; 372; 2521-32. • Randomized controlled phase 3 study • Advanced melanoma with at least 1 prior chemotherapy, any BRAF status • 834 patients, 1:1:1 ratio • Pembrolizumab every 2 weeks vs pembrolizumab every 3 weeks vs ipilimumab every 3 weeks • Primary endpoint: Progression free survival (PFS) • Secondary endpoints: Overall survival (OS) and adverse events (AEs).
- 22. NEJM 2015; 372; 2521-32. Pembrolizumab every 2wks Pembrolizumab every 3wks Ipilimumab every 3 wks 6 month PFS 47.3% 46.4% 26.5% 12 month OS 74.1% 68.4% 58.2% Response rate 33.7% 32.9% 11.9% G3/4 AES 13.3% 10.1% 19.9%
- 24. • Open label phase 3 study • Previously treated advanced nonsmall cell lung CA (majority had no EGFR mutations / ALK translocation) • 1034 patients, 1:1:1 ratio • Pembrolizumab 2 mg/kg vs pembrolizumab 10 mg /kg vs docetaxel • Primary endpoint: Overall survival (OS) and progression free survival (PFS) • Secondary endpoints: Adverse events (AEs), determination of PDL1 receptor expression www.thelancet.com Published online December 19, 2015 http://dx.doi.org/10.1016/S0140-6736(15)01281-7
- 25. www.thelancet.com Published online December 19, 2015 http://dx.doi.org/10.1016/S0140-6736(15)01281-7 Pembrolizumab 2 mg / kg Pembrolizumab 10 mg / kg Docetaxel 75 mg / kg Median OS 10.4 months (14.9 months if PDL1 >50%) 12.7 months (17.3 months if PDL1 >50%) 8.7 months (8.2 months if PDL1 >50%) Median PFS 3.9 months 4.0 months 4.0 months G3/5 AES 13.0% 16.0% 35.0%
- 27. Outside the Philippines… • Pembrolizumab is approved for: 1. First-line treatment of advanced / metastatic NSCLC 2. Recurrent / Metastatic Head and Neck SCCA 3. MSI-High Colorectal Cancer 4. Relapsed / Refractory Classical Hodgkin’s Lymphoma after Failure of Brentuximab 5. Second-line treatment for Advanced Urothelial Carcinoma
- 32. Published online at NEJM.org, February 17, 2017. • Open label phase 3 study • Previously treated advanced / metastatic urothelial carcinoma • At least 10% PD-L1 positive • 542 patients, 1:1 ratio • Pembrolizumab 200 mg every 3 weeks vs investigator’s choice of chemotherapy • Primary endpoint: Overall survival (OS) and progression free survival (PFS) • Secondary endpoints: Adverse events (AEs)
- 33. Published online at NEJM.org, February 17, 2017. Pembrolizumab 200 mg every 3wks Investigator’s Choice of Chemotherapy Median PFS (p=0.42) 2.1 months 3.3 months Median OS (p=0.005) 10.3 months 7.4 months G3/5 AES 15.0% 49.4%
- 34. Side effect profile • Hyperactive immune system 1. Hypothyroidism / hyperthyroidism (6-9%) 2. Pneumonitis (4-7%) 3. Colitis (1-3%) 4. Infusion reactions (3-6%) 5. Nephritis (<2%) 6. Severe skin reactions (2-6%) 7. Adrenal insufficiency (<2%) 8. Myositis (1-3%) 9. Hypophysitis (<2%) 10. Pancreatitis (<2%) 11. Autoimmune hepatitis (<1%) 12. Uveitis (<1%) • Others: pruritus, asthenia, diarrhea, fatigue, anemia, decreased appetite, pyrexia, stomatitis • BUT NO: alopecia, neutropenia, neuropathy, thrombocytopenia
- 35. Published online November 2016. • HYPERPROGRESSIVE DISEASE (HPD): RECIST progression at the first evaluation and as a >/= 2 fold increase in tumor growth rate • Retrospective study of phase I trials • 9% had HPD • Associated with older age and shorter survival • In another study: The amplification of MDM2 is also associated with hyperprogression after the initiation of immunotherapy.The pace of progression was increased anywhere from 5-40 fold.
- 36. In a nutshell • Immunotherapy can be in the form of vaccines, CAR T- cells, IL-2 and checkpoint inhibitors. • For pembrolizumab: when PD-1 integrates with PD-L1,an IMMUNOSTAT is produced that leads to T-cell inactivation and reduced tumor cell killing. • Blocking this pathway will free the cytotoxic T- lymphocytes and facilitate tumor cell killing. • PD-1 inhibitors are effective and have a favorable side effect profile. • Further studies are ongoing that will guide us on appropriate patient selection.
- 37. Thank you!
Editor's Notes
- #10: Next is through transfer of T cells, or what we know now as CART cell therapy.
- #12: Just 2 months ago, a case report was published that with the help of CAR T-cells, multifocal glioblastoma regressed in size.
- #16: .
- #17: Wherein a T cell can just be beside a cancer cell and do nothing, instead of acting against it.
- #18: The most popular of the CTLA4 inhibitors is IPILIMUMAB. This is the study that got ipilimumab its FDA approval for metastatic melanoma in 2010. It randomized 676 patients into ipilimumab plus a vaccine vs the vaccine alone, vs ipilimumab alone. Median overall survival with ipilimumab alone was 10.1 months and it showed no difference with the combination arm. Prior to this study, after chemotherapy patients would onl live for less than 3 months so this was a big development for the field of melanoma.
- #19: In 2013, several phase 1 and 2 trials came out with very promising results. PD1/PDL1 antagonists were labelled as the drug of the year because long term tumor control was now achievable.
- #20: In 2015, we entered the era of PD-1 inhibitors, nivolumab and pembrolizumab as their PHASE III data came out. These are what we commonly refer to now as IMMUNOTHERAPY. But actually, in the previous decades, we have already been giving immunotherapy, but with different targets. In the interest of time, I will not be discussing trials on Nivolumab as it is not available in the Phils.
- #21: Prior to making this presentation, I asked the MSD product lead what the approved indications were in the Philippines and this is what I got for an answer. Presently, it is only approved for metatstatic melanoma and nonsmall cell lung cancer who have progressed on chemotherapy.
- #22: This study investigated pembrolizumab vs ipilimumab in patients with advanced melanoma who had received at least 1 prior chemotherapy. The primary endpoint was progression free survival and secondary endpoints were overall survival and adverse events
- #23: Pembrolizumab was superior to ipilimumab in terms of progression free and overall survival. Response rate more than doubled and severe adverse events were less frequently reported.
- #24: Because of that pivotal paper, pembrolizumab was incoprporated in our guidelines and considered as standard of care.
- #25: The next study investigated pembrolizumab vesus docetaxel in previously treated, PDL1 positive advanced nonsmall cell lung cancer. It was an open label phase 3 study, where they also determined the PDL1 status of the tumors
- #26: Summarized are the results: For unselected patients, pembrolizumab was better than chemotherapy in terms of overall survival and progression free survival. It also had a better side effect profile. When they examined the degree of PDL1 expression, they noted that those patients with a PDL1 expression of more than 50% had the most benefit in terms of survival. Patients were living up to 17 months on pembrolizumab vs 8 months on chemotherapy.
- #27: Shown here is the incorporation of immunotherapy in lung cancer second line.
- #28: To summarize again, here it is only approved for metastatic melanoma and for lung cancer second line. Outside the Philippines, Pembro is approved for the following indications
- #29: Pembro is already approved as first line for lung cancer provided that it does not harbor any mutations and translocations and its PDL1 expression is more than 50%. It received category 1 recommendation.
- #30: It is also approved for recurrent/netastatic/unresectable head and neck squamous cell cancer on or after chemotherapy.
- #35: In the pivotal papers that were published that had pembrolizumab approved for its specific indications, there was no report of heart failure. But Dr De los Reyes will likely discuss that