"" Ralph Moss—Cancer Consultant: 2018-10-07

Friday, October 12, 2018


Human lymphocyte, electron micrograph
(Source: Wikimedia Commons)

One of the most important questions about immune checkpoint inhibitor (ICI) therapy is who will respond to this new type of treatment. A recent paper from the University of Texas M.D. Anderson Cancer Center, Houston, has now established a "prognostic scoring system" to help select such patients.

The system is based on an analysis of 172 patients with metastatic cancer who were enrolled in phase I clinical trials: 105 of them received anti-CTLA-4 drugs, while the rest received anti-PD-1 agents.(Sen, 2018a).

The authors identified seven factors that predicted who would respond best. I have taken the liberty of rearranging these by their hazard ratios (HR), which indicates the increased risk of death associated with each factor:
  1. An absolute lymphocyte count under 1,800 cells per microliter [hazard ratio, HR = 3.3]
  2. An ECOG performance status greater than 1 [HR = 2.81]
  3. An elevated neutrophil count greater than 4,900 [HR = 2.3]
  4. An elevated serum lactate dehydrogenase (LDH enzyme) greater than 466 [HR = 2.1]
  5. The presence of liver metastases [HR = 1.8]
  6. An elevated platelet count over 300,000 [HR = 1.8]
  7. An age of over 52 years [HR = 1.59]
The authors next pooled the patients into four separate groups, based on the number of risk factors that they had. There was a huge difference in overall survival (OS) among these four risk groups:
  1. Group One had 0-2 risk factors: overall survival (OS) = 24.2 months
  2. Group  Two had 3 risk factors = 11.6 months OS
  3. Group Three had 4 risk factors = 8.0 months OS
  4. Group Four was defined as those having 5 or more factors = 3.8 months overall survival (OS)
In those who had zero, one or at most two risk factors, the median survival was thus over two years: and about half of that group was still alive three years after receiving immune therapy. In fact, none of these patients had died after their two-year anniversary of starting treatment. In assessing these figures, remember that all of the patients in this study had advanced disease and had enrolled in these phase I trials as what one might call a "Hail Mary pass" treatment.

Let's now talk about the most important risk factor, the absolute lymphocyte count.

Lymphocytes are a sub-set of white blood cells (leukocytes) that are particularly involved in fighting infections and cancer. In this study, an absolute lymphocyte count under 1,800 cells per microliter (µL) turned out to be the biggest risk factor for failing to respond to ICI therapy. According to the NIH, the normal range of total lymphocytes in an adult is between 1,000 and 4,800 per microliter of blood (µL). But in this study any score under 1,800 µL conveyed a hazard ratio of 3.3 to patients receiving immunotherapy. This is logical, since ICI drugs work by activating the lymphocytes. One would therefore suppose that having fewer lymphocytes would diminish the positive effects of the treatment. But this M.D. Anderson study gives scientific validation of that logical conclusion.

This of course leads to the question of what might cause a decline in the absolute number of lymphocytes. This paper does not discuss the causes of the various risk factors. But one possible cause is cytotoxic chemotherapy, the backbone of the medical treatment of cancer around the world. According to a paper from the Head of the Immunology Section of the National Cancer Institute (NCI):
"Although neutrophil, monocyte, and platelet numbers consistently recovered to greater than 50 percent of pretreatment values after each sequential cycle of [chemo]therapy, lymphocyte numbers did not recover within the same time period...." (Mackall C, 1994, emphasis added)
Lymphocyte depletion following chemotherapy has been well known to oncologists for decades, although many websites addressed to patients underplay the impact of chemotherapy on lymphocytes. For example, an article at the breastcancer.org website claims:
"After finishing chemotherapy treatment, it can take anywhere from about 21 to 28 days for your immune system to recover."
No references are given for this statement. Yet a 2016 study in Breast Cancer Research looked at the long-term impact of chemotherapy on various types of lymphocytes, including B cells, T cells and NK (natural killer) cells:
"Levels of B, T and NK cells [three types of lymphocytes, ed.] were significantly reduced 2 weeks after chemotherapy.... B cells demonstrated particularly dramatic depletion, falling to 5.4 percent of pre-chemotherapy levels. Levels of all cells recovered to some extent, although B and CD4(+) T cells remained significantly depleted even 9 months post-chemotherapy.... ... Breast cancer chemotherapy is associated with long-term changes in immune parameters..." (emphasis added).
Thus, damage may continue for many months, not just a few weeks. While there are a number of possible causes of depleted lymphocytes, in many cancer patients the cause will be cytotoxic chemo as well as radiation therapy. Yet patients are frequently given all possible cytotoxic treatments before doctors will even consider immunotherapy.

It is important to note that this same group at M.D. Anderson also demonstrated that lower doses of immune checkpoint drugs may reduce both toxicity and cost without compromising disease control or survival (Sen, 2018b). [I discuss this in a previous blog.]

In addition, these drugs are enormously expensive. The maximum cost of a single anti-CTLA-4 drug ipilimumab (Yervoy®) is now over USD $1.7 million per patient! (Goldstein, 2017) As a result, this type of therapy is simply not affordable for most people around the world. One can speculate that with better patient selection, and lower doses of ICI, this treatment could become much more affordable for both the individual and society as a whole. This would realistically fulfill the promise of the famous immunologist Carl H. June, MD, that the present moment is only "the tip of the iceberg" of effective immunotherapy of cancer (June, 2017).


Acknowledgement: My thanks to Tibor Bakacs, MD, PhD, DSc, of the Hungarian Academy of Sciences, Budapest, for his contributions to this blog post.


Goldstein DA. Adjuvant ipilimumab for melanoma—the $1.8 million per patient regimen. JAMA Oncology. 2017;3:1628.

June CH., Warshauer JT, Bluestone JA. Is autoimmunity the Achilles' heel of cancer immunotherapy? Nat Med. 2017;23:540.

Mackall CL, Fleisher TA, Brown MR, et al. Lymphocyte depletion during treatment with intensive chemotherapy for cancer. Blood. 1994;84:2221.

Shiraj Sen, et al. Development of a prognostic score system for patients with advanced cancer enrolled in immune checkpoint inhibitor phase I clinical trials. British Journal of Cancer. 2018; 118:763-769 [2018a].

Sen S, Hess KR, Hong DS, et al. Impact of immune checkpoint inhibitor dose on toxicity, response rate, and survival: A pooled analysis of dose escalation phase 1 trials. Journal of Clinical Oncology. 2018;36:3077 [2018b].

Sunday, October 7, 2018


Kleef clinic, Vienna, Austria

Many of my phone consultees are surprised to hear me say that lower doses of immune checkpoint inhibitor (ICI) drugs are often as effective as the more typical higher doses, with far less toxicity.

Won’t a lower-dose regimen, they wonder, be less effective than the high-dose regimens recommended by the US Food and Drug Administration (FDA) and the drug manufacturers? Well, apparently not. This question was studied in an analysis of clinical trial, which was presented at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO). Here are the conclusions from the University of Texas M.D. Anderson Cancer Center, Houston (home institution of the co-discoverer of immune checkpoint inhibitors):
“Despite a dose-dependent increase in irAE [immune-related adverse events, ed.], we identify no improvement in PFS [progression-free survival, ed.], OS [overall survival, ed.], or DCR [disease control rate, ed.] with escalating doses of ICI [immune checkpoint inhibitors, ed.]...Lower doses may reduce toxicity and cost without compromising disease control or survival."

This is an enormously important finding, which has gotten very little attention in the media. But it is a confirmation of the approach of Ralf Kleef, MD, of Vienna, Austria, who claims excellent results using a lower-than-typical dose of ICI drugs, with far fewer serious side effects, especially when the ICIs are integrated into a holistic immune-stimulating protocol.