Tag Archives: vaccine

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 ≥30% shrinkage of their tumors, but overall results were disappointing with only 11% of patients having ≥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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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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