Tag Archives: vaccine

Immuno-Fighting Cancer Like Wildfires


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I live in what is now known as the urban wildland interface west of Denver, the kind of area prone to the devastating fires that have been scorching California. Our firewise community efforts have taught us a lot about how a single windblown ember from miles away can destroy your house, and many of us have done a lot of mitigation. But, if the “big one” comes, our best hope is to grab the family albums and head down the hill.

Cancer can be very similar. If someone walks in with widespread disease, unless it is one of the highly treatable ones like testis cancer, flying over the patient with flame retardant (chemotherapy) may delay things for a while, but often the home is lost. The earliest realization of how to do better may have come from breast cancer. William Halstead realized¬†in 1894 that putting out the fire effectively might include getting the surrounding “embers” (lymph nodes) at the time of removing the primary breast tumor (campfire in this analogy). A century later, it had become clear that in many instances the embers had spread too far for more radical surgical approaches, but that in some cases the embers could be extinguished (adjuvant chemotherapy) before the fire got out of control.

But what if the fire could be self-extinguishing? What if there was a boy scout at the campfire with a fire extinguisher? Better yet, what if you had smoke jumpers who could parachute in and help the boy by putting out the small fires elsewhere started by the embers? Immunotherapy offers just such hope. In the 1980’s we learned that giving high dose IL-2 to some patients with particularly sensitive tumors (kidney, melanoma) could produce cures in some cases. I liken this to sending in a group of non-specialist firemen/women in huge numbers to fight the forest fire doing the best they can.

Sending these individuals to more specialized training resulted in Provenge (sipuleucel-T), the first “vaccine” approved for treating any cancer, prostate being the target, and I was fortunate to participate in some of the first trials of this approach. But what was needed was both more effective equipment (in this case the PD-1 inhibitors that can “extinguish” the cancer’s ability to turn off the immune response) and more highly trained firefighters (potentially think of CAR-T cells) who have advanced skills, graduate degrees from a university, and can be deployed to go in search of the embers.

Now to torture this analogy just a bit further, let’s imagine that rather than sending the firefighters to universities for advanced generalized training, we could send them to CIA camps where they would receive the most specialized training possible right at the site where the fire started. In cancer, this may be the idea of using cryotherapy or irreversible electroporation to kill the local tumor, then injecting some cocktail of immune stimulatory molecules that enhance the body’s ability to create very effective T-cells that can go out as smoke jumpers looking for the embers (metastases), without the need for the university training outside the body (Sip-T or CAR-T).

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Already there are clinical trials underway with this technique that show promise. Gary Onik has demonstrated some remarkable responses in metastatic prostate cancer patients. Diwakar Davar just presented similarly exciting data in high risk melanoma patients who received intratumoral CMP-001 and systemic nivolumab before resection of the primary tumors. 62% of the patients had no tumor left in their surgical specimens! So ¬†the cancer/firefighters are out there and although there will always be wildfires we simply can’t extinguish, the prospects for controlling them before or soon after they have spread have never looked better.

 

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Filed under General Prostate Cancer Issues, Targeted treatment

[How to] Choose Your Own Adventure


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Back when Al Gore and I invented the internet (just kidding…but it does seem like a long time ago – before twitter, instagram, and all the rest), I had the privilege of helping my professional society create its first website, ASCO Online. As part of that effort, I wrote an introductory article to assist my colleagues in understanding what I felt lay in the future. In addition to trying to explain how browsers and the internet worked (as an amateur early adopter), I stated, “Oncologists will increasingly act as information guides rather than information resources for patients and their families with cancer.”

Herein, I will attempt to make that easier for you if you have a personal interest in prostate cancer. There are now more than 103 million “hits” in a google search for “prostate cancer”. Therefore, first understand your condition. If you are thinking about screening, put that in your search term, or read this article I selected for you.

Next, be familiar with the myriad of terms that have evolved to describe different situations (“states”, “stages”, “conditions” etc.) to describe the disease. “Localized” means you have prostate cancer that is felt to be (or even proven to be after surgery) confined to the prostate. If localized, is it high risk, intermediate risk, or low risk? Your physician should be able to help you understand this based on the Gleason score, pathology findings, and PSA, but there are now multiple molecular tests that can be done to help further characterize what has been found. There is an excellent article to help you understand these here. If you haven’t had surgery or radiation, and are just deciding what to do, some of these tests can be done on your biopsy. I once wrote a blog about the challenging decision of choosing a method of primary treatment that is still relevant here.

However to be really up to date, you may wish to look at the research going on for any of the more advanced prostate cancer conditions. For this, you should become familiar with and use the NIH website, Clinicaltrials.gov. To help you with this, I have done some preliminary searches for different conditions, but recognize that the terms you enter change what you see, so regard this as just a start. Pick your condition, and click on it and you will find some trials that are ongoing (I preselected “recruiting”) for some common situations. If you don’t see your situation, play with the search terms yourself.

High risk after surgery based on pathology
Rising PSA (biochemical failure) after surgery or radiation
Known metastatic disease (spread to bones or nodes on scans) never previously treated
Rising PSA or new metastases on scans while on hormone therapy

Now, taking the last example which gave links to 160 studies, you can narrow the search results by using the pull down menu on the search screen, starting with country. Note that limiting to the U.S. drops the available trials from 160 to 93. Adding the state, Colorado, drops it to 14 studies, etc. Maybe you have a relative in a certain city or state you could visit if a trial fits your situation. If you would like to look only at immunotherapy trials, try entering the term, “immunotherapy”.

Next, let’s go further into one trial. Let’s say we are interested in the NIH immunotherapy trial being conducted at the NCI. If you scroll down, you can see what will be involved:

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Next, since the devil is in the details, you need to know if you are eligible for this trial. Continue to scroll down to the Eligibility Criteria section. Here you find what clinical conditions you MUST have (Inclusion Criteria) or MUST NOT have (Exclusion Criteria).

At this point, you should understand how it would be almost impossible for your physician to stay up on all of the trials. YOU are now the “information guide” and if you are interested in whether a certain trial (or even an approach you have found that might be something you could do outside of a trial) could be useful in your case, you should make an appointment to speak with your doctor about the trial/approach. Recognize that this will probably take more time than your “usual visit” and notify the clinic you will want extra time to discuss this. Print out the relative parts of the trial so you can show it to her/him, and ideally have your meeting in an exam room with an internet-connected computer so you can search through details together. If there are questions, each trial has the phone number for a contact person (typically a research nurse), and since your physician may be able to answer questions you would have trouble finding in your record, this phone call is best made together from the exam room.

In our fast-moving, internet-enabled era of medicine, this is how I think medicine should be practiced. The shared burden of “keeping up” means the patient has to do his (no women have prostate cancer) or her (if you are a supportive spouse or similar) own research, help the doctor, and work on approaches as a team. Being respectful of the time involved is critical, but it CAN work. And it is much more rewarding than keeping up with tweet storms!! And if this is “not for you”, find a grandchild and choose some different adventures here. (disclaimer: I have never done this, but looks like it could be fun)

 

 

 

 

 

 

 

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An Amateur Explanation of Immunotherapy


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For as long as I can remember, there has been lurking excitement regarding the possibility that our immune systems can find and destroy cancer cells. The history of well-documented spontaneous remissions goes back decades and is briefly reviewed here. I have personally never seen a spontaneous remission of cancer, although I have had patients who have done far better than anyone would have expected, suggesting that something must have slowed down their tumor progression.

In prostate cancer, one of the early hints that it might be possible to stimulate an immune attack on the disease came from the studies on Provenge (Sipuleucel-T). My colleagues and I placed several patients on the trials that led to approval of this “vaccine” by the FDA. These studies have continued to demonstrate improved survival of patients with metastatic disease who have failed hormone therapy, although the trials were all done before the availability of the newer ADT drugs abiraterone, enzalutamide, and apalutamide. On the other hand, in spite of the optimistic data we obtained in another vaccine trial on a product known as prostvac, the pivotal trial to prove efficacy failed. It is possible that the vaccine produced modest efficacy, but the signal was drowned out by treatment with the new ADT agents.

As anyone who watches the evening news or other TV-ad-saturated programs aimed at us seniors, other cancers – especially melanoma, lung, bladder, kidney and a few additional ones have been more “easily” treated with newer immune therapies known as check point inhibitors. The idea here is that our normal immune system has built in “braking systems”, the best studied and clinically utilized to date being the PD-1/PDL-1 mechanism. If we immunize you against, for example, measles – you want a vigorous immune response, but you don’t want your entire immune system to keep working on fighting measles. There are other threats it needs to be on guard against. Shutting down the T-cells that fight viruses and cancer involves the Programed Death receptor-1 on these T-cells with a specific protein,¬†Programed Death receptor Ligand-1. Cancer cells can take advantage of initiating this same braking system by releasing their own PDL-1 that will kill the incoming tumor-fighting T-cell. This devious cancer mechanism to avoid our immune systems can be blocked by therapeutic antibodies directed against either the receptor or the PDL-1 ligand protein.

At the recent ASCO meeting, it was revealed that selected metastatic lung cancer patients who have an activated PD-1/PDL-1 braking system are now more effectively treated with pembrolizumab (Keytruda) than chemotherapy. It is emerging that the subgroup of patients who have tumors that are genetically highly unstable, (regardless of tumor type) with lots of mutations leading to abnormal proteins that can stimulate an immune response, may all benefit from PD-1/PDL-1 directed therapy. These patients, including prostate cancer patients can be identified by testing their tumors for microsatellite instability or mismatch repair deficiency. At a practical level, however, when and how to test prostate cancers for such biomarkers remains challenging. Last week at the ASCO annual meeting, Dr. De Bono from the UK reported results on treating patients with metastatic prostate cancer who had progressed on hormones and chemotherapy (docetaxel) with pembrolizumab. 17/163 patients had ‚Č•30% shrinkage of their tumors, but overall results were disappointing with only 11% of patients having ‚Č•50% decline in PSA. Testing for the presence of PDL-1 was not particularly predictive of which patient would benefit most. However, this way of treating prostate cancer will eventually lead to important progress in my opinion. Combining vaccines with the checkpoint inhibitors is currently being studied, and there are other checkpoint drugs and targets that are in development as well. Timing the checkpoint drugs with hormonal therapy or radiation therapy may also find optimal ways of stimulating an immune response. The field of immuno-oncology is an exciting new frontier and well worth keeping your eyes on.

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Filed under General Prostate Cancer Issues, Prostate cancer therapy, Targeted treatment

Prostate cancer advances – The Oscars are in…


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I have been attending the ASCO led GU oncology symposium for the last 48 hours. As usual, it is somewhat of a “firehose to take a drink” scenario with great presentations, more posters than you can possibly absorb, and lots of progress on many fronts. I remember when there were only about 50 “GU oncologists” 30 years ago, and about 300 attended this meeting when it first started. The attendance is 2900 from around the world. As one of my patients likes to put on his blog, “help is on the way”, which is really encouraging. There is more to report than I can possibly do in a blog, so I will just poach from existing internet info and highlight some of the existing¬†posts.

Chemotherapy for newly diagnosed patients with many metastases is now the “standard of care” following the CHAARTED trial that I previously discussed. The French completed a smaller study that did NOT show an advantage for using docetaxel “up front”. There are a number of possible explanations that you can read about here. Not mentioned in that discussion is a moderately complex explanation that came up in the discussion period after the presentation. It turns out that ADT leads to changes in the way docetaxel is metabolized. Thus, the approval of the use of docetaxel in the setting of castrate resistant pca (which has been the usual situation) is different from using docetaxel when a patient hasn’t been on ADT for very long. The French study had more toxicity, and potentially more delays in treatment but the relationship of when the ADT started may have been different from the CHAARTED trial and could explain differences. Nevertheless, CHAARTED was larger and I think the trial still sets a new standard.

The optimal duration of ADT when given to enhance radiation was covered extensively by Anthony D’amico. The details are pretty complex, and if you want to wade into these weeds, you can start with his JCO article. Basically, the issue is this: ADT helps radiation therapy be more effective. But it is clearly “toxic” in terms of quality of life, and possibly increases cardiac events in men with a history of heart disease. Both of these factors make it questionable to use at all in men with “low intermediate risk” disease, and we would certainly like to use for as little time as necessary to get the benefit so that quality of life is preserved. In the higher risk patients there is no doubt that it should be used, but the duration is still up for discussion, with the existing “definitive” study showing 36 months is better than 6 months. Generally in such patients, I go over this, and then say, “let’s see how well you tolerate ADT before we reach any final decision on how long to continue”. Certainly a minimum of 4 months is required, and possibly the longer the better, but I suspect 36 months is too long. And really no one has taken into account the factor that a single 3 month leuprolide injection can result in quite variable overall duration of testosterone suppression with older men generally not recovering as quickly as the younger guys.

On the vaccine front, data were presented on Prostvac in combination with the immune checkpoint inhibitor, ipilumimab. The exciting findings in using checkpoint inhibitors (including the PD1 and PDL1 drugs in other diseases has lagged somewhat in prostate cancer because it isn’t clear that the ongoing immune response is very good. (For example ipi alone in prostate cancer didn’t work) However, given the promising data on using Prostvac in the phase II trials, the phase III trial has now accrued all of its patients and we await the result. Meanwhile, investigators have begun to look at whether adding a checkpoint inhibitor to a vaccine can make further headway. An abstract presented at the meeting reported on the early results of this approach. Dr. Singh from the NCI GU oncology team stated “In a Phase 1 combination study of 30 mCRPC patients with similar baseline characteristics (predicted median OS of 18.5 months), patients were treated with PROSTVAC plus escalating doses of ipilimumab. The observed median OS was 31.3 months for all dose cohorts and 37.2 months for patients treated at 10 mg/kg based on updated overall survival data. Furthermore, there appears to be a tail on the curve with approximately 20% of patients at 10 mg/kg alive at 80 months.” This certainly means that if the Phase III trial of Prostvac leads to approval by the FDA, there will quickly be more studies of how to make this vaccine even more effective.

Many of us have been talking at this meeting and other recent meetings about a “kitchen sink” approach combining all of the newer drugs to get a biochemical complete response in metastatic patients and then using a vaccine to “clean up” the microscopic disease that is clearly left behind. I’m looking forward to these trials which are probably a year or two away, but optimism abounds. Example: A new man with metastatic disease who had prostate radiation or surgery 5 years ago is found because of a rising PSA. We do fancy scans with C-11 acetate or choline, radiate the known disease, treat with second generation ADT plus docetaxel x 6, then use the vaccine with a checkpoint inhibitor. (read that link by the way – terrific) Given that prostate cancer is generally a “slow cancer”, there are many men alive today with lurking metastases that will only become apparent 5 or 10 years from now. These guys will almost certainly be able to take advantage of such an approach – never fast enough, but never more promising prospects, either.

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