Webinar	Immunotherapy of Breast and Pancreatic Cancers
Presenter	Dr. Elizabeth Jaffee, Johns Hopkins
Publisher	Cancer Research Initiative
Links	[Webinar] [Publisher]

Overview

In this blog post, Immunotherapy of Pancreatic Cancer – a Webinar, I’m annotating a webinar for information I think is useful to pancreatic cancer patients. My goal is to make the information more accessible. Towards that end, drugs mentioned are in bold font, and links are provided to additional information, such as research papers, research results, and clinical trials mentioned in the webinar. The webinar information is presented in a table, ordered by time index, with a brief description of the content from the webinar. My interpretation of Dr. Jaffee’s presentation could be incorrect in some areas, so your own healthcare professional’s interpretations should supersede mine.

The Jun 13, 2013 webinar annotated in this posting is from the Cancer Research Institute (CRI) Breakthroughs in Cancer Immunotherapy webinar series. The CRI is a “nonprofit organization dedicated exclusively to harnessing the immune system’s power to conquer all cancers”.

The presenter, Dr. Elizabeth Jaffee, MD [papers], is a Johns Hopkins medical oncologist specializing in vaccine therapies for pancreatic cancer and other solid tumors.

Readers of this blog should note that I am a participant in one of Dr. Jaffee’s immunotherapy clinical trials (NCT01088789) for resected pancreatic cancer patients, receiving a single dose of cyclophosphamide and the GVAX vaccine at each treatment session.

Key Points for Patients

• Immunotherapy of pancreatic cancer is currently only available through clinical trials
• Immunotherapy drug targets can be applied to more than one type of cancer
• This webinar focuses largely on the GVAX vaccine that Dr. Jaffee helped develop
• Some immunotherapy clinical trial results are presented

Time	Description
2:02	Introduction of Dr. Elizabeth Jaffee
3:31	Aduro Biotech has licensed the GVAX and Listeria vaccines
4:58	List of technical advances that enabled recent immunotherapy progress
5:44	Ipilimumab (Yervoy), FDA approved for melanoma, targets the CTLA-4 protein receptor on the immune T cell so it can recognize the cancer cell as foreign. Believes that it can also work in pancreatic cancer (see Time Index 24:43 and NCT00836407).
7:01	PD-1/PD-L1 mAb (monoclonal antibodies), similar to Ipilimumab, inhibits signals on T cells that prevent them from fighting cancer
7:31	Listing of new immunotherapy treatments
7:55	The targets on immune cells are not tumor type [site of origin] specific. The same principles can be applied to other cancers, such as pancreatic cancer. [DD: The idea of treating cancers by their genetic differences rather than site of origin is being discussed as a major treatment change - see: targeted therapies]
8:31	Biomarkers are being developed to identify patients that will respond to a particular immunotherapy. [Paper: Lymphocyte Counts in GVAX]
8:55	Explanation (with graphic) of how pancreatic cancer develops. Describes genetic and immune system changes over time [Figure].
9:17	Describes a gradual progression of genetic changes. In pancreatic cancer, one of the first changes is a mutation of KRAS.
10:12	The tumor cells induce some bad changes in the immune response that help the cancer to grow.
11:26	Microscopic view of resected patient's pancreatic cancer showing tumor cells and stroma. The cancer cells attract the regulatory T cells (Tregs, the wrong kind of immune cells) [DD: these Treg cells prevent the right kind of immune cells from getting to the cancer cells. Later GVAX clinical trials added cyclophosphamide to engage the Treg cells and allow the right immune cells to get into the tumor].
12:14	Slide and explanation of the tumor's immune-related environment. The CD8+ T cells (a type of effector T cell that has the CD8 protein on its surface) are the ones we need to attack the tumor.
13:14	The dendritic cell (DC) can active or suppress T cells in attacking cancer cells. Drugs that inhibit signals such as CTLA-4 and PD-1 keep the dendritic cells from stopping the T cells from doing their work.
14:33	Slide showing how the GVAX vaccine and cyclophosphamide work together to bring CD8+ T cells to tumor cells. [2008 Paper][2009 Paper] The GVAX vaccine containing tumor cells genetically modified to produce GM-CSF is injected just below the skin. The body's dendritic cells detect the GM-CSF emitted by these tumor cells as foreign. The dendritic cells travel to the lymph nodes where they activate T cells to recognize this new foreign invader. The newly activated CD8+ T cells leave the lymph nodes in search of tumor cells. In earlier clinical trials without cyclophosphamide, the Treg cells would intercept the CD8+ T cells before reaching the tumor cells After recognizing what was happening, a low dose cyclophosphamide was added to the regimen to engage the T reg cells and allow the CD8+ T cells to get to the tumor cells.[Paper]
15:35	Mesothelin is one of the proteins on the tumor's surface that is targeted by the immune cells. Mesolthelin levels on the tumor help predict disease-free survival time (DFS) [2004 Paper][2008 Paper][2011 Paper]. [DD: The explanation is not clear here, but I think the finding correlating mesothelin levels on the tumor and DFS is for patients in general (no vaccine)]
17:01	Results of 60 patient clinical trial [NCT00084383, Johns Hopkins, NCI] using GVAX (alone) [Paper] that observed improved DFS and that long-term survivors developed an immune response to mesothelin [Figure]. It takes at least 4 vaccine treatments to get to the point of high immune response to mesothelin.
18:27	GVAX vaccine clinical trial [NCT00727441, Johns Hopkins, NCI] where first treatment is given 2 weeks prior to surgery. The removed tumor is examined for effects from the vaccination. Lymphocytes activated against the cancer are seen under the microscope [Paper]. [DD: Why aren't more studies done like this? Seeing the effect in a human with cancer is optimal!]
19:44	The resected patient's immune cells (lymphoid aggregates) that were attacking the tumor cells are genetically sequenced to see what they were targeting on the cancer tumor cells.
21:04	Case study of clinical trial participant that then joined a follow-up/boost study [NCT01088789, Johns Hopkins] whose CT and PET scan appeared to show a recurrence, despite the patient feeling great. Patient went to surgery and the resected tissue showed inflammation with immune cells and no tumor. Theorized that the tumor was coming back and the immune system took it out.
22:55	A 22-patient Pfizer-sponsored UPenn study [NCT00711191, Pfizer, Hoffman-La Roche, U Penn] of metastatic pancreatic cancer patients using gemcitabine and an agonist CD40 antibody (CP-870893). The CD40 protein activation stimulates T cells to make them work better [Paper]. The study showed a significant reduction in tumor mass in some metastatic patients after 3 cycles [Figure].
24:43	A Johns Hopkins phase Ib clinical trial [NCT00836407, Johns Hopkins] using ipilimumab with/without GVAX vaccine on metastatic pancreatic cancer patients [Paper] [Survival]. Researchers note that after treatment the tumors sometimes start to grow first (inflammation response) and then necrose later, tracking with the CA19-9 levels [Figure].
27:32	5-10 more years to get the best vaccines into the clinics. The best time to use these vaccines is during early disease (pre-malignancy), like the HPV vaccine for cervical cancer [DD: I've noted that some researchers believe that using chemotherapy plus vaccines on late-stage cancer patients can buy you enough time for the vaccines to take hold and do their thing].
29:34	Johns Hopkins is developing a new vaccine without pancreatic cancer tumor cells that can still alert dendritic cells (using listeria monocytogenes bacteria). You don't want to give pancreatic cancer cell lines to innoculate people without pancreatic cancer.
30:13	Clinical trial [NCT01417000, Aduro BioTech, Johns Hopkins] of GVAX vaccine + Cyclophosphamide with/without CRS-207 for metastatic patients is seeing great responses [ASCO][Poster][Paper].
32:37	Based on the mouse tests, it looks like they'll be ready to try a preventative vaccine in high-risk humans in 2-3 years.
33:16	Individual patient mutation vaccines: soon we'll be able to sequence a tumor and develop a vaccine targeting that patient's mutations [Ref?].
33:37	A Phase I study [NCT01897415 or NCT02159716, U Penn] using a genetically-engineered T cell vaccine (CARS). The patient's own T cells are extracted, genetically modified to respond to mesothelin, grown/multiplied in the lab, and reinserted into the patient. They are causing a lot of tumor regressions in patients who otherwise had no hope for a response to cancer.
36:38	Q: What are some of the best places in the USA for cutting-edge treatment of pancreatic cancer? A: Johns Hopkins MD Anderson (not much immunotherapy) UCSF U Penn Sloan Kettering [DD: Not sure, but this answer may have been mostly directed towards best treatment centers with immunology programs]
37:32	Q: Should patients be concerned about these immunotherapies causing autoimmune responses? A: Experienced institutions are getting good at recognizing the signs of autoimmune responses and can intervene. [DD: Subsequent comments by Dr. Jaffee indicate that they may not have seen all the kinds of autoimmune responses and that they need to learn how to turn off the vaccine after it's job is done]