Background: Despite antiretroviral therapy (ART), people with HIV continue to exhibit immune deficits including failure to fully reconstitute CD4 T cell numbers and function, resulting in increased risks of tumors and infections and reduced response to vaccination. Pomalidomide, a derivative of thalidomide (IMID), has immunomodulatory properties that may be beneficial in this setting. We explored its impact on lymphocyte number and activation in patients with and without HIV treated within a prospective clinical trial for Kaposi sarcoma.

Methods: Patients received pomalidomide 5mg orally for 21 days of 28 day cycles. Assessments were performed every 4 weeks for lymphocyte numbers, Kaposi sarcoma associated herpesvirus (KSHV/HHV8) viral load (VL) and HIV VL and at 8 weeks for T cell subsets and activation by immunophenotyping of peripheral blood mononuclear cells (PBMC). KSHV VL in PBMC and HIV VL in plasma were assayed by quantitative PCR; for HIV VL we used an ultrasensitive single copy assay. Changes from baseline were evaluated using the Wilcoxon signed rank test with P<0.005 considered significant given multiple comparisons. Differences in changes between the HIV infected and uninfected groups were evaluated using the Wilcoxon rank sum test. Study registered as NCT1495598.

Results: 19 patients (12 HIV infected, 7 uninfected) median age 50 years (range 32-74) were studied. All with HIV were receiving ART for median 48 months (7-227), HIV VL 1.5 copies/mL (<0.5–37), and CD4 378 cells/µl (135–752). At week 4 and 8 of therapy we observed significant increases in CD4 and CD8 counts, with a decline in CD19 B cells and no change in NK cells or HIV VL. A transient increase in KSHV VL was seen at week 4, not sustained at week 8:

Abstract 4128. Table 1
ParameterBaseline (cells/µl unless noted)Change to Week 4
(Med, range)
PChange to Week 8 (Med, range)P
CD3 1143 (525–2305) +264 (-419–1524) 0.0028 +210 (-496–1455) 0.0020 
CD4 429 (135–1171) +107 (-87–650) 0.0009 +86 (-37–491) 0.0015 
CD8 495 (259–1529) +108 (-271–915) 0.0085 +155 (-495–834) 0.0046 
NK 184 (28–557) +30 (-130–117) 0.52 +2 (-174–127) 0.98 
CD19 139 (9–322) -47 (-117–76) 0.0039 -79 (-169–62) <0.0001 
KSHV VL  0 copies/PBMC (0–8750) +23 (-92–5250) 0.0098 0 (-92–20850) 0.31 
Plasma HIV VL
(infected pts) 
1.5 copies/mL (<0.5–37) +0.3 (-1.5–3.0) 0.75 +0.75 (0–28) 0.13 
ParameterBaseline (cells/µl unless noted)Change to Week 4
(Med, range)
PChange to Week 8 (Med, range)P
CD3 1143 (525–2305) +264 (-419–1524) 0.0028 +210 (-496–1455) 0.0020 
CD4 429 (135–1171) +107 (-87–650) 0.0009 +86 (-37–491) 0.0015 
CD8 495 (259–1529) +108 (-271–915) 0.0085 +155 (-495–834) 0.0046 
NK 184 (28–557) +30 (-130–117) 0.52 +2 (-174–127) 0.98 
CD19 139 (9–322) -47 (-117–76) 0.0039 -79 (-169–62) <0.0001 
KSHV VL  0 copies/PBMC (0–8750) +23 (-92–5250) 0.0098 0 (-92–20850) 0.31 
Plasma HIV VL
(infected pts) 
1.5 copies/mL (<0.5–37) +0.3 (-1.5–3.0) 0.75 +0.75 (0–28) 0.13 

In addition, at week 8 both CD4 and CD8 T cells showed significant increases in activation (CD38+, HLADR+ and DR+/38+) and decreases in senescence (CD57+). Both also showed a significant shift towards increased central memory (CM) and away from naive (N) and effector (E) phenotypes, with no change in effector memory (EM) cells:

Abstract 4128. Table 2
CD4 SubsetsBaseline (%)
(med, range)
Absolute Change in % at Week 8 (med, range)P
RO- 27+ (N) 32.6 (13.3–76.5) -6.6 (-35.8–21.6) 0.002 
RO+ 27+ (CM) 41.9 (13.6–63.6) +6.4 (-15.5–32.5) 0.027 
RO+ 27- (EM) 16.7 (4.6–31.7) +1.7 (-7.2–21.0) 0.28 
RO- 27- (E) 3.3 (0.4–14.3) -1.5 (-5.7–0.3) 0.0004 
38+ 34.5 (11.2–67.3) +4.3 (-13.0–19.4) 0.024 
HLA DR+ 8.9 (3.3–25.0) +8.3 (0.7–19.5) <0.0001 
38+ DR+ 2.5 (0.6–11.7) +2 (-1.0–8.1) <0.0001 
57+ 6.3 (0.6–26.6) -1.34 (-16.2–7.6) 0.034 
CD8 Subsets    
RO- 27+ (N) 21.0 (9.7–70.4) -5.1 (-13.7–14.3) 0.019 
RO+ 27+ (CM) 17.1 (2.5–37.9) +8.1 (-8.4–18.6) 0.0047 
RO+ 27- (EM) 18.4 (4.6–40.8) +1.0 (-9.4–44.9) 0.35 
RO- 27- (E) 31.8 (4.1-63.7) -6.1 (-47.3–22.5) 0.01 
38+ 33.4 (8.3–66.0) +19.9 (-0.8–40.6) <0.0001 
HLA DR+ 19.6 (5.0–46.4) +11.6 (-4.7–32.1) 0.0001 
38+ DR+ 8.0 (0.4–33.3) +8.5 (0.1–22.6) <0.0001 
57+ 30.8 (2.9–72.9) -11.0 (-28.5–6.1) <0.0001 
CD4 SubsetsBaseline (%)
(med, range)
Absolute Change in % at Week 8 (med, range)P
RO- 27+ (N) 32.6 (13.3–76.5) -6.6 (-35.8–21.6) 0.002 
RO+ 27+ (CM) 41.9 (13.6–63.6) +6.4 (-15.5–32.5) 0.027 
RO+ 27- (EM) 16.7 (4.6–31.7) +1.7 (-7.2–21.0) 0.28 
RO- 27- (E) 3.3 (0.4–14.3) -1.5 (-5.7–0.3) 0.0004 
38+ 34.5 (11.2–67.3) +4.3 (-13.0–19.4) 0.024 
HLA DR+ 8.9 (3.3–25.0) +8.3 (0.7–19.5) <0.0001 
38+ DR+ 2.5 (0.6–11.7) +2 (-1.0–8.1) <0.0001 
57+ 6.3 (0.6–26.6) -1.34 (-16.2–7.6) 0.034 
CD8 Subsets    
RO- 27+ (N) 21.0 (9.7–70.4) -5.1 (-13.7–14.3) 0.019 
RO+ 27+ (CM) 17.1 (2.5–37.9) +8.1 (-8.4–18.6) 0.0047 
RO+ 27- (EM) 18.4 (4.6–40.8) +1.0 (-9.4–44.9) 0.35 
RO- 27- (E) 31.8 (4.1-63.7) -6.1 (-47.3–22.5) 0.01 
38+ 33.4 (8.3–66.0) +19.9 (-0.8–40.6) <0.0001 
HLA DR+ 19.6 (5.0–46.4) +11.6 (-4.7–32.1) 0.0001 
38+ DR+ 8.0 (0.4–33.3) +8.5 (0.1–22.6) <0.0001 
57+ 30.8 (2.9–72.9) -11.0 (-28.5–6.1) <0.0001 

There were no significant changes in Ki67 or PD-1 expression in either CD4 or CD8 cells. There was no significant difference between HIV infected and uninfected patient groups in the observed effects on any parameter including cell number and phenotype.

Conclusions: Pomalidomide induced significant increases in the number of CD4 and CD8 T cells and the proportion of activated and central memory cells and decreased senescence in both HIV infected and uninfected subjects. Effects were not explained by alterations in HIV viremia. The transient early rise in KSHV VL may reflect reactivation of latent infection and enhance immune killing of KSHV infected cells. This analysis sheds light on possible mechanisms of IMID activity in viral-associated tumors. As the first study of immune modulation by IMIDs in vivo in people with HIV it also suggests exploration of IMIDs to augment immune responsiveness in HIV and other immunodeficiencies is warranted.

Disclosures

Polizzotto:Celgene Corporation: Research Funding. Off Label Use: Pomalidomide for Kaposi sarcoma. Uldrick:Celgene Corporation: Research Funding. Zeldis:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Yarchoan:Celgene Corporation: Research Funding.

Author notes

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Asterisk with author names denotes non-ASH members.

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